WO2017018804A1 - 1,3,4-oxadiazole amide derivative compound as histone deacetylase 6 inhibitor, and pharmaceutical composition containing same - Google Patents

Abstract

The present invention relates to: a novel compound having a histone deacetylase 6 (HDAC6) inhibitory activity; an optical isomer thereof or a pharmaceutically acceptable salt thereof; a use thereof for preparing a therapeutic pharmaceutical preparation; a pharmaceutical composition containing the same and a treatment method using the composition; and a preparation method therefor. According to the present invention, the novel compound and the optical isomer thereof or pharmaceutically acceptable salt thereof have histone deacetylase 6 (HDAC6) inhibitory activity and are effective in preventing or treating HDAC6-associated diseases including: infectious diseases; neoplasm; endocrine, nutritional and metabolic diseases; psychological and behavioral disorders; neurological disorders; eye and adnexa diseases; circulatory system diseases; respiratory system diseases; digestive system diseases; skin and subcutaneous tissue diseases; musculo-skeletal system and connective tissue diseases; or congenital malformations, deformations and chromosomal abnormalities.

Description

1,3,4-oxadiazole amide derivative compound as histone deacetylase 6 inhibitor and pharmaceutical composition comprising the same

The present invention provides a 1,3,4-oxadiazole amide derivative compound having a histone deacetylase 6 (HDAC6) inhibitory activity, an optical isomer thereof, a pharmaceutically acceptable salt thereof; Their use for the manufacture of therapeutic agents; Treatment method using these; Pharmaceutical compositions containing them; And methods for their preparation.

Post-translational modifications such as acetylation in cells are very important regulatory modules at the center of biological processes and are tightly controlled by many enzymes. Histones are the central proteins that make up chromatin. They act as a winding axis for DNA, helping to condense DNA. In addition, the balance between acetylation and deacetylation of histones plays a very important role in gene expression.

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from the histone protein lysine residues that make up chromatin. They are associated with gene silencing and cell cycle arrest and angiogenesis. It is known to induce inhibition, immunomodulation, cell death (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). In addition, inhibition of HDAC enzyme function has been reported to induce cancer cell self-killing by lowering the activity of cancer cell survival-related factors and activating cancer cell death-related factors in vivo (Warrell et al, J. Natl. Cancer Inst. 1998). , 90, 1621-1625).

In humans, 18 HDACs are known and classified into four classes according to homology with yeast HDACs. The eleven HDACs that use cofactors as zinc are Class I (HDAC1, 2, 3, 8), Class II (IIa: HDAC4, 5, 7, 9; IIb: HDAC6, 10) and Class IV (HDAC11). It can be divided into three groups. In addition, seven HDACs of Class III (SIRT 1-7) use NAD ⁺ as a cofactor instead of zinc (Bolden et al., Nat. Rev. Drug Discov. 2006, 5 (9), 769-784).

While various HDAC inhibitors are in preclinical or clinical development, only non-selective HDAC inhibitors are known to be anticancer agents to date, and vorinostat (SAHA) and romidepsin (FK228) are the treatments for cutaneous T-cell lymphoma. panobinostat (LBH-589) has been approved for the treatment of multiple myeloma. However, non-selective HDACs inhibitors are generally known to have side effects such as fatigue and nausea at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). These side effects have been reported to be due to the inhibition of class I HDACs, and non-selective HDACs inhibitors have been limited in drug development in fields other than anticancer drugs (Witt et al., Cancer Letters 277 (2009) 8.21). ).

On the other hand, selective class II HDAC suppression has been reported to not show the toxicity seen in class I HDAC suppression, and development of selective HDAC inhibitors may resolve side effects such as toxicity by non-selective HDAC inhibition. Selective HDAC inhibitors are likely to be developed as effective therapeutic agents for various diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).

HDAC6, one of the Class IIb HDACs, is mainly present in the cytoplasma and is known to be involved in the deacetylation of many non-histone substrates (HSP90, cortactin, etc.), including tubulin proteins (Yao). et al., Mol. Cell 2005, 18, 601-607). HDAC6 has two catalytic domains and the C-terminal zinc finger domain can bind ubiquitinated proteins. Because HDAC6 contains a large number of non-histone proteins as substrates, various diseases include cancer, inflammatory diseases, autoimmune diseases, neurological diseases, and neurodegenerative disorders. (Santo et al., Blood 2012 119: 2579-258; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).

Common structural features of various HDAC inhibitors are composed of a cap group, a linker group, and a zinc binding group (ZBG), as shown in the structure of vorinostat below. Many researchers have investigated the inhibitory activity and selectivity for enzymes through structural modifications of the cap and linker groups. Among these, zinc-binding groups are known to play a more important role in enzyme inhibitory activity and selectivity (Wiest et al., J. Org. Chem. 2013 78: 5051-5065; Methot et al., Bioorg. Med. Chem. Lett. 2008, 18, 973-978).

Most of the zinc-binding groups are hydroxamic acid or benzamide, and the double hydroxamic acid derivatives exhibit potent HDAC inhibitory effects but have low bioavailability and severe off-target activity. -target activity) Since benzamide contains aniline, there is a problem of generating toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).

Thus, unlike non-selective inhibitors with side effects for the treatment of cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative disorders, etc. There is a need for the development of selective HDAC6 inhibitors having zinc-binding groups with improved bioavailability without side effects.

It is an object of the present invention to provide 1,3,4-oxadiazole amide derivative compounds, optical isomers thereof or pharmaceutically acceptable salts thereof having selective HDAC6 inhibitory activity.

Another object of the present invention is to provide a pharmaceutical composition comprising a 1,3,4-oxadiazole amide derivative compound having selective HDAC6 inhibitory activity, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

Yet another object of the present invention is to provide a method for producing these.

Another object of the present invention is to infectious diseases, neoplasms, endocrine, nutritional and metabolic diseases, mental and behavioral disorders, neurological diseases, eye and appendages diseases, circulatory diseases, respiratory diseases, digestive diseases, skin and subcutaneous tissue diseases To provide a pharmaceutical composition comprising the above compounds for the prevention or treatment of diseases related to HDAC6 activity, including musculoskeletal and connective tissue diseases or congenital malformations, modifications and chromosomal abnormalities.

Another object of the present invention is to provide the use of the compounds for the preparation of a medicament for the prevention or treatment of diseases associated with HDAC6 activity.

It is another object of the present invention to provide a method for the treatment of a disease associated with HDAC6 activity comprising a therapeutically effective amount of a pharmaceutical composition comprising said compounds.

The present inventors have discovered the present invention by finding a 1,3,4-oxadiazole amide derivative compound having a histone deacetylase 6 (HDAC6) inhibitory activity and using it to inhibit or treat a disease related to HDAC6 activity. Completed.

1,3,4- Oxadiazole Amide  Derivative compounds

According to the above object, the present invention provides a 1,3,4-oxadiazole amide derivative compound represented by the following formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

In Chemical Formula I,

L ₁ , L ₂ or L ₃ are each independently-(C ₀ -C ₂ alkyl)-;

Z ₁ to Z ₄ are each independently N or CR ^Z

{Wherein Z ₁ to Z ₄ may not be three or more at the same time N,

R ^Z Is -H or -X};

R ₁ is —CX ₂ H or —CX ₃ ;

,

또는

이고 R ₂ is-(C ₁ -C ₄ alkyl),-(C ₁ -C ₄ alkyl) -O (C ₁ -C ₄ alkyl),-(C ₁ -C ₄ alkyl) -C (= O) -O (C ₁ -C ₄ alkyl),-(C ₃ -C ₆ cycloalkyl), -aryl, -heteroaryl or

,

or

ego

Wherein one or more H of-(C ₃ -C ₆ cycloalkyl), -aryl or -heteroaryl is -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl ), -C (= O) - (C 1 -C 4 alkyl), -C (= O) -0 (C 1 -C ₄ can be substituted with alkyl), or -CF _3,

Y is -N-, -O- or -S (= O) _2- ,

When Y is -N-, R ₄ and R ₈ are each independently -H,-(C ₁ -C ₄ alkyl), -C (= O)-(C ₁ -C ₄ alkyl), -C (= O)-(C ₃ -C ₆ cycloalkyl), -C (= 0) -0 (C ₁ -C ₄ alkyl), -C (= 0) -CF ₃ , -S (= 0) _2- (C ₁ -C ₄ alkyl),-(C ₂ -C ₆ heterocycloalkyl), benzyl or amine protecting group, wherein-(C ₂ -C ₆ heterocycloalkyl) contains N, O or S atoms in the ring Can do this],

When Y is -O- or -S (= O) _2- , R ₄ and R ₈ are nothing (null),

R ₅ to R ₈ are each independently —H, — (C ₁ -C ₄ alkyl), —OH, —CH ₂ OH or —C (═O) —NH ₂ ,

a to c are each independently an integer of 1, 2 or 3;

또는

이고R ₃ is -H,-(C ₁ -C ₄ alkyl),-(C ₁ -C ₄ alkyl) -O (C ₁ -C ₄ alkyl),-(C ₁ -C ₄ alkyl) -C (= 0 ) -O (C ₁ -C ₄ alkyl),-(C ₃ -C ₆ cycloalkyl), -aryl, -heteroaryl,

or

ego

{Wherein at least one H of-(C ₃ -C ₆ cycloalkyl), aryl or heteroaryl is each independently -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl), -C (= O) - (C 1 -C 4 alkyl), -C (= O) -0 (C 1 -C _4, and may be substituted with alkyl), or -CF _3,

R ₄ , R ₅ , R ₆ , Y, a, b, R ₁ , L ₁ , Z ₁ , Z ₂ , Z ₃ and Z ₄ are as defined above; And

X is F, Cl, Br or I.

In addition, according to a preferred embodiment of the present invention, the compound represented by Formula (I),

In Chemical Formula I,

L ₁ and L ₃ are-(C ₀ alkyl)-;

L ₂ is-(C ₁ -C ₂ alkyl)-;

Z ₁ to Z ₄ are each independently N or CR ^Z

{Wherein Z ₁ to Z ₄ may not be two or more N at the same time,

R ^Z Is -H or -X};

R ₁ is —CX ₂ H or —CX ₃ ;

,

또는

이고R ₂ is — (C ₁ -C ₄ alkyl),-(C ₃ -C ₆ cycloalkyl), -aryl, -heteroaryl,

,

or

ego

Wherein one or more H of-(C ₃ -C ₆ cycloalkyl), -aryl or -heteroaryl is -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl ), -C (= O) - (C 1 -C 4 alkyl), -C (= O) -0 (C 1 -C ₄ can be substituted with alkyl), or -CF _3,

Y is -N-, -O- or -S (= O) _2- ,

When Y is -N-, R ₄ and R ₈ are each independently -H,-(C ₁ -C ₄ alkyl), -C (= O)-(C ₁ -C ₄ alkyl), -C (= _{O) -CF 3, -S (=} O) 2 - (C 1 -C 4 alkyl), - (C ₂ -C ₆ heterocycloalkyl), -C (= O) - (C 3 -C 6 cycloalkyl ), Benzyl or amine protecting group, wherein-(C ₂ -C ₆ heterocycloalkyl) may contain an O atom in the ring},

When Y is -O- or -S (= O) _2- , R ₄ and R ₈ are nothing (null),

R ₅ to R ₈ are each independently —H, — (C ₁ -C ₄ alkyl), —OH, —CH ₂ OH or —C (═O) —NH ₂ ,

a to c are each independently an integer of 1, 2 or 3;

R ₃ is -aryl or -heteroaryl

{Wherein at least one H of aryl or heteroaryl is each independently -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl), -C (= 0)-( C ₁ -C ₄ alkyl), -C (= 0) -0 (C ₁ -C ₄ alkyl) or -CF ₃ ; And

X is F, Cl, Br or I.

In addition, according to a more preferred embodiment of the present invention, the compound represented by the formula (I),

In Chemical Formula I,

L ₁ and L ₃ are-(C ₀ alkyl)-;

L ₂ is-(C ₁ alkyl)-;

Z ₁ to Z ₄ are each independently N or CR ^Z

{Wherein Z ₁ to Z ₄ may not be two or more N at the same time,

R ^Z Is -H or -X};

R ₁ is —CF ₂ H or —CF ₃ ;

이고R ₂ is — (C ₁ -C ₄ alkyl), -pyridinyl or

ego

Wherein one or more H of -pyridinyl is -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl), -C (= 0)-(C ₁ -C ₄ alkyl), -C (= O) -0 (C 1 -C _4, and may be substituted with alkyl), or -CF _3,

Y is -N-,

R ₄ is — (C ₁ -C ₄ alkyl), —C (═O)-(C ₁ -C ₄ alkyl) or -S (═O) _2- (C ₁ -C ₄ alkyl),

R ₅ or R ₆ are each independently —H or — (C ₁ -C ₄ alkyl),

a and b are each independently an integer of 1 or 2};

R ₃ is -aryl

Wherein one or more H of aryl may each independently be substituted with -X; And

X is F, Cl, Br or I.

According to a particularly preferred embodiment of the present invention, the compound represented by the formula (I) is

In Chemical Formula I,

L ₁ and L ₃ are-(C ₀ alkyl)-;

L ₂ is-(C ₁ alkyl)-;

Z ₁ to Z ₄ are each independently N or CR ^Z

{Wherein Z ₁ to Z ₄ may not be two or more N at the same time,

R ^Z Is -H or -X};

R ₁ is —CF ₂ H or —CF ₃ ;

이고R ₂ is -pyridinyl or

ego

Wherein one or more H of -pyridinyl is -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl), -C (= 0)-(C ₁ -C ₄ alkyl), -C (= O) -0 (C 1 -C _4, and may be substituted with alkyl), or -CF _3,

Y is -N-,

R ₄ is — (C ₁ -C ₄ alkyl), —C (═O)-(C ₁ -C ₄ alkyl) or -S (═O) _2- (C ₁ -C ₄ alkyl),

R ₅ or R ₆ are each independently -H,

a and b are each independently an integer of 1 or 2;

R ₃ is -aryl

Wherein one or more H of aryl may each independently be substituted with -X; And

X is F, Cl, Br or I.

Specific compounds represented by Formula I of the present invention are shown in Table 1 below:

In the present invention, the compound represented by the formula (I), its optical isomer or pharmaceutically acceptable salt thereof is compound 11110, 11189, 11233, 11237, 11238, 11239, 11240, 11241, 11242, 11243, 11245, 11327, 11332, 11333, 11334, 11339, 11341, 11359, 11360, 11376, 11414, 11418 and 11419, preferably selected from the group consisting of compounds 11189, 11233, 11239, 11241, 11242, 11243, 11333, 11334, 11341, 11359 More preferably, 11360, 11376, 11414, 11418 and 11419.

In the present invention, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, and include, for example, inorganic ion salts made of calcium, potassium, sodium and magnesium; Inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid and sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid Organic acid salts prepared with acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid and the like; Sulfonic acid salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and naphthalenesulfonic acid; Amino acid salts prepared with glycine, arginine, lysine and the like; And amine salts made of trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like, but the salts used in the present invention are not limited by these salts.

Preferred salts in the present invention include hydrochloride, phosphate, sulfate, trifluoroacetate, citrate, bromate, maleate or tartarate, and preferred examples of such compounds are compounds 11022, 11136 and 11137 herein.

The compounds represented by formula (I) of the present invention may contain one or more asymmetric carbons and may therefore exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and respective diastereomers. have. Such isomers can be separated by prior art, for example, compounds represented by the formula (I) by separation such as column chromatography or HPLC. Alternatively, the stereoisomers of each of the compounds represented by Formula I can be stereospecifically synthesized using optically pure starting materials and / or reagents in known arrangements.

1,3,4- Oxadiazole Amide  Preparation of Derivative Compound

The present invention provides a method for preparing a 1,3,4-oxadiazole amide derivative compound represented by the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof.

Preferred methods for preparing the 1,3,4-oxadiazole amide derivative compound represented by the formula (I), its optical isomers or pharmaceutically acceptable salts thereof are shown in Schemes 1 to 5, and modified to levels apparent to those skilled in the art. The manufacturing method also includes this.

Scheme 1

[Scheme 1] is a method for synthesizing a compound having an amide structure, the formula 1-1 is a reductive amination reaction with an amine compound, or the formula 1-2 is substituted with an amine compound to prepare a formula 1-3. Formula 1-3 is reacted with acyl chloride of Formula 1-4 to prepare Formula 1-5, and reacted with hydrazine to prepare Formula 1-6. Thereafter, the reaction product is reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare Chemical Formula 1-7. In this case, when the oxadiazole ring is not formed as in Chemical Formula 1-8, 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent) is reacted to prepare Chemical Formula 1-8.

Compounds prepared by the above schemes are 11022, 11105, 11106, 11107, 11108, 11109, 11110, 11188, 11189, 11246, 11247, 11339, 11340, 11341, 11356, 11357, 11358, 11359, 11360, 11376 and 11584 .

Scheme 2

[Scheme 2] is a method for synthesizing a compound having a heterocycloalkyl amide structure, by reacting the formula (2-1) with an amine compound to prepare the formula (2-2), and by the substitution reaction to produce a formula 2-3. Formula 2-3 is prepared by reacting Formula 2-3 with hydrazine. Thereafter, the compound is reacted with trifluoroacetic anhydride or difluoroacetic anhydride to synthesize Formula 2-5. In this case, when the oxadiazole ring is not formed as in Compound 2-6, the compound is reacted with 1-methoxy-N-triethylammoniosulfonyl-methaneimide (Burgess reagent) or methanesulfonyl chloride. To prepare a formula (2-7) by removing the protecting group of formula (2-5). Compound 2-8 was prepared by reacting compound 2-7 with aldehyde, acyl chloride, sulfonyl chloride, acetic anhydride, oxetan-3-one, and the like.

Compounds prepared by the above scheme are 11134, 11135, 11136, 11137, 11138, 11139, 11140, 11141, 11142, 11143, 11157, 11158, 11159, 11160, 11161, 11162, 11163, 11164, 11165, 11166, 11187, 11200 , 11201, 11202, 11203, 11204, 11205, 11206, 11207, 11208, 11209, 11210, 11211, 11212, 11213, 11214, 11215, 11232, 11233, 11234, 11235, 11236, 11237, 11238, 11239, 11240, 11241 , 11242, 11243, 11244, 11245, 11325, 11326, 11327, 11328, 11329, 11330, 11331, 11332, 11333, 11334, 11621 and 11622 .

Scheme 3

[Scheme 3] is a method for synthesizing a compound having a heterocycloalkyl amide structure, to remove the protecting group of the formula 2-3 to produce the formula 3-4, to prepare a formula 3-5 by the reductive amination reaction. . Formula 3-5 is prepared by reacting Formula 3-5 with hydrazine. Thereafter, the reaction mixture was reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare Formula 3-8.

Compounds prepared by the above schemes are 11414, 11418 and 11419 .

Scheme 4

[Scheme 4] is a method for synthesizing a compound having a heterocycloalkyl amide structure, the formula 4-1 is reacted with an amine compound to prepare the formula 4-2, and the substitution reaction to produce the formula 4-3. Formula 4-3 is reacted with hydrazine to produce formula 4-4. Subsequently, it is reacted with difluoroacetic anhydride to synthesize Formula 4-5. Formula 4-6 is prepared by removing the protecting group of formula 4-5, and reacted with methanesulfonyl chloride to prepare formula 4-7. Chemical Formula 4-8 is prepared by reacting Chemical Formula 4-7 with a substituted cycloamine. Further, Chemical Formula 4-9 is prepared by reaction with Chemical Formula 4-7 and morpholine, thiomorpholine, or piperazine derivatives. In this case, unsubstituted piperazine was reacted with sulfonyl chloride, acetic anhydride or oxetan-3-one to prepare compound 4-10.

Compounds prepared by the above schemes are 11534, 11535, 11536, 11537, 11538, 11610, 11611, 11612, 11613 and 11614 .

Scheme 5

[Scheme 5] is a method for synthesizing a compound having a heterocycloalkyl amide structure, and reacting the formula (5-1) with an amine compound to produce a formula (5-2), the substitution reaction to prepare a formula (5-3). Formula 5-3 is reacted with hydrazine to prepare Formula 5-4. Thereafter, Chemical Formula 5-5 was synthesized by reacting with trifluoroacetic anhydride or difluoroacetic anhydride and reacted with methanesulfonyl chloride to prepare Chemical Formula 5-6.

Compounds prepared by the above schemes are 11602 and 11603 .

1,3,4- Oxadiazole Amide  Compositions Comprising Derivative Compounds, Uses thereof, and Methods of Treatment Using the Same

The present invention is a pharmaceutical composition for the prevention or treatment of diseases related to histone deacetylase 6 activity containing a compound represented by the following formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient To provide.

[Formula 1]

Formula I is as defined above.

The pharmaceutical composition of the present invention exhibits significant effects in the prevention or treatment of diseases associated with histone deacetylase 6 activity by selectively inhibiting histone deacetylase 6.

Diseases associated with histone deacetylase 6 activity include infectious diseases such as prion disease; Benign tumors (e.g. myelodysplastic syndrome) or malignant tumors (e.g. multiple myeloma, lymphoma, leukemia, lung cancer, colon cancer, colon cancer, prostate cancer, urinary epithelial cancer, breast cancer, melanoma, skin cancer, liver cancer, brain cancer, stomach cancer Neoplasms such as ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer or glioma); Endocrine, nutritional and metabolic diseases such as Wilson's disease, amyloidosis or diabetes; Mental and behavioral disorders such as depression or Rett syndrome; Central nervous system atrophy (e.g. Huntington's disease, spinal muscular atrophy (SMA), spinal cerebellar ataxia (SCA)), neurodegenerative diseases (e.g. Alzheimer's disease), motor disorders (e.g. Parkinson's disease), neuropathy (e.g. Hereditary neuropathy (Sarco-Marie-Tooth disease), sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy, motor neuron disease (eg, atrophic lateral sclerosis (ALS)), or central nervous system demyelination ( Neurological diseases such as, for example, multiple sclerosis (MS)); Eye and appendage diseases such as uveitis; Circulatory diseases such as atrial fibrillation or stroke; Respiratory diseases such as asthma; Digestive diseases such as alcoholic liver disease, inflammatory bowel disease, Crohn's disease or ulcerative bowel disease; Skin and subcutaneous tissue diseases such as psoriasis; Musculoskeletal and connective tissue diseases such as rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus (SLE); Or congenital malformations, modifications, and chromosomal abnormalities, such as autosomal dominant polycystic neoplasia, in addition to symptoms or diseases associated with abnormal function of histone deacetylase.

The pharmaceutically acceptable salts are as described above in the pharmaceutically acceptable salts of the compounds represented by formula (I) of the present invention.

The pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the compound represented by the formula (I), the optical isomer thereof or the pharmaceutically acceptable salt thereof for administration. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added. Diluents, dispersants, surfactants, binders and lubricants may also be added in addition to formulate into injectable formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Thus, the compositions of the present invention may be patches, solutions, pills, capsules, granules, tablets, suppositories, and the like. These formulations may be prepared by conventional methods used in the art for formulation or by methods disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, and formulated into various formulations depending on the individual disease or component. Can be.

The composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The daily dosage of the compound represented by the formula (I) of the present invention is about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and may be administered once to several times a day.

The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicaments in addition to the compound represented by the formula (I), the optical isomer thereof or the pharmaceutically acceptable salt thereof.

The present invention provides a method for preventing or treating a disease related to histone deacetylase 6 activity comprising the administration of a therapeutically effective amount of a compound represented by formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Provide a way to.

As used herein, the term “therapeutically effective amount” refers to an amount of a compound represented by the formula (I) effective for the prevention or treatment of a disease associated with histone deacetylase 6 activity.

The present invention also provides a method for selectively inhibiting HDAC6 by administering a compound represented by Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof to a mammal including human.

The method for preventing or treating a histone deacetylase 6 activity-related disease of the present invention, by administering a compound represented by the formula (I), not only treats the disease itself before the manifestation of the symptoms, but also inhibits the symptoms thereof. It also includes doing or avoiding. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. Dosage and frequency of dose will vary depending on the age, weight and response of the individual patient. Appropriate dosage regimens can be readily selected by those of ordinary skill in the art that naturally consider such factors. In addition, the method of preventing or treating a histone deacetylase 6 activity-related disease of the present invention, together with the compound represented by the formula (1) of the therapeutically effective amount of an additional active agent to help treat the disease It may further comprise administration, wherein the additional active agent may exhibit a synergistic or adjuvant effect with the compound of formula (I).

The present invention also provides the use of a compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease associated with histone deacetylase 6 activity. . The compound represented by the formula (I) for the preparation of a medicament may be mixed with an acceptable adjuvant, diluent, carrier and the like, and may be prepared in a complex formulation with other active agents to have a synergistic action of the active ingredients.

The matters mentioned in the uses, compositions and methods of treatment of the invention apply equally unless they contradict each other.

The compound represented by the formula (I), the optical isomer thereof or a pharmaceutically acceptable salt thereof of the present invention may selectively inhibit HDAC6, thereby preventing or treating a histone deacetylase activity related disease. Is remarkably excellent.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, these Examples etc. are only illustrations of this invention, The scope of the present invention is not limited only to these.

1,3,4- Oxadiazole Amide  Preparation of Derivative Compounds

Specific preparation method of the compound of formula (I) is as follows.

Example 1 Synthesis of Compound 11022, N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) isonicotinamide

[Step 1] Synthesis of methyl 4-((phenylamino) methyl) benzoate

A solution of aniline (1.961 mL, 21.475 mmol), methyl 4-formylbenzoate (4.230 g, 25.770 mmol) and acetic acid (0.614 mL, 10.738 mmol) in methylene chloride (50 mL) was stirred at 0 ° C. for 10 min. Sodium triacetoxyborohydride (6.828 g, 32.213 mmol) was added and further stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (4.730 g, 91.3%) as a colorless oil.

[Step 2] Synthesis of Methyl 4-((N-phenylisonicotinamido) methyl) benzoate

Methyl 4-((phenylamino) methyl) benzoate (0.150 g, 0.622 mmol) prepared in step 1, isonicotinyl chloride hydrochloride (0.221 g, 1.243 mmol) and N, N-diisopropylethylamine (0.194 mL, 1.243 mmol) was dissolved in methylene chloride (10 mL) at room temperature and stirred for 1 hour at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.179 g, 83.1%) as a white solid.

[Step 3] Synthesis of N- (4- (hydrazinecarbonyl) benzyl) -N-phenylisonicotinamide

Methyl 4-((N-phenylisonicotinamido) methyl) benzoate (0.179 g, 0.517 mmol) and hydrazine hydrate (0.488 mL, 10.335 mmol) prepared in step 2 were mixed with ethanol (10 mL) and irradiated with microwaves. After heating at 120 ° C. for 1 hour, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0% to 15%) to give the title compound (0.134 g, 74.9%) as a white solid.

[Step 4] Synthesis of Compound 11022

N- (4- (hydrazinecarbonyl) benzyl) -N-phenylisonicotinamide (0.105 g, 0.303 mmol) prepared in step 3, trifluoroacetic anhydride (0.051 mL, 0.364 mmol) and triethylamine (0.084 mL, 0.606 mmol) was dissolved in methylene chloride (20 mL) at room temperature and stirred at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0% to 30%) to give the title compound (0.035 g, 26.1%) as a white foamy solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, 2H, J = 5.8 Hz), 8.06 (d, 2H, J = 8.3 Hz), 7.49 (d, 2H, J = 8.2 Hz), 7.28-7.14 (m, 5H), 6.98-6.82 (m, 2H), 5.17 (d, 2H, J = 19.0 Hz); LRMS (ES) m / z 425.2 (M ⁺ +1).

[Step 5] Synthesis of Compound 11022 Hydrochloride

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) isonicotinamide (0.100 g, 0.236 mmol) prepared in step 4 To the solution dissolved in dichloromethane (10 mL) at room temperature was added hydrochloric acid (1.00 M solution in ethyl acetate, 0.259 mL, 0.259 mmol) and stirred at the same temperature for 1 hour. After removing the solvent from the reaction mixture under reduced pressure, ethyl acetate (2 mL) was added to the concentrate, followed by stirring. The precipitated solid was filtered, washed with ethyl acetate solution and dried to give the title compound (0.108 g, 99.5%) as a white solid. Got it.

Example 2: Synthesis of Compound 11105, N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) acetamide

[Step 1] Synthesis of methyl 4-((N-phenylacetamido) methyl) benzoate

Acetyl chloride (0.088 mL) in a solution of methyl 4-((phenylamino) methyl) benzoate (0.200 g, 0.829 mmol) and diisopropylethylamine (0.290 mL, 1.658 mmol) in methylene chloride (10 mL) at room temperature. 1.243 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.220 g, 93.7%) as a white solid.

[Step 2] Synthesis of N- (4- (hydrazinecarbonyl) benzyl) -N-phenylacetamide

Methyl 4-((N-phenylacetamido) methyl) benzoate (0.220 g, 0.776 mmol) and hydrazine hydrate (0.733 mL, 15.530 mmol) prepared in step 1 were mixed with ethanol (10 mL) and irradiated with microwaves. After heating at 120 ° C. for 2 hours, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / methylene chloride = 0% to 15%) to give the title compound (0.145 g, 65.9%) as a white foamy solid.

[Step 3] Synthesis of N-phenyl-N- (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) acetamide

N- (4- (hydrazinecarbonyl) benzyl) -N-phenylacetamide (0.145 g, 0.512 mmol) and triethylamine (0.142 mL, 1.024 mmol) prepared in step 2 were methylene chloride (10 mL) at room temperature. To the solution dissolved in trifluoroacetic anhydride (0.087 mL, 0.614 mmol) was added and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.180 g, 92.7%, yellow foamy solid).

[Step 4] Synthesis of Compound 11105

N-phenyl-N- (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) acetamide (0.180 g, 0.475 mmol) prepared in step 3 and 1- Methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.170 g, 0.712 mmol) was mixed with tetrahydrofuran (10 mL), irradiated with microwaves, heated at 150 ° C. for 30 minutes, and then the temperature was increased. The reaction was terminated by lowering to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 50%) to afford the title compound (0.088 g, 51.3%) as light yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, 2H, J = 8.3 Hz), 7.47-7.13 (m, 5H), 7.02 (dd, 2H, J = 7.8, 1.5 Hz), 4.98 (s, 2H), 1.93 (s, 3H); LRMS (ES) m / z 362.3 (M ⁺ +1).

Example 3: Synthesis of Compound 11106, N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) cyclohexanecarboxamide

[Step 1] Synthesis of methyl 4-((N-phenylcyclohexanecarboxamido) methyl) benzoate

Methyl 4-((phenylamino) methyl) benzoate (0.200 g, 0.829 mmol) and N, N-diisopropylethylamine (0.290 mL, 1.658 mmol) were dissolved in methylene chloride (10 mL) at room temperature in a cyclo Hexanecarbonyl chloride (0.166 mL, 1.243 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.285 g, 97.8%) as a white solid.

[Step 2] Synthesis of N- (4- (hydrazinecarbonyl) benzyl) -N-phenylcyclohexanecarboxamide

Methyl 4-((N-phenylcyclohexanecarboxamido) methyl) benzoate (0.285 g, 0.811 mmol) and hydrazine hydrate (0.766 mL, 16.219 mmol) prepared in step 1 were mixed in ethanol (10 mL) After microwave irradiation and heating at 120 ° C. for 2 hours, the reaction was terminated by lowering the temperature to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0% to 15%) to give the title compound (0.239 g, 83.9%) as a white foamy solid.

[Step 3] Synthesis of N-phenyl-N- (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) cyclohexanecarboxamide

N- (4- (hydrazinecarbonyl) benzyl) -N-phenylcyclohexanecarboxamide (0.239 g, 0.680 mmol) and triethylamine (0.189 mL, 1.360 mmol) prepared in step 2 were methylene chloride at room temperature. Trifluoroacetic anhydride (0.115 mL, 0.816 mmol) was added to the solution dissolved in (10 mL) and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.300 g, 98.6%, white foamy solid).

[Step 4] Synthesis of Compound 11106

N-phenyl-N- (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) cyclohexanecarboxamide (0.300 g, 0.670 mmol prepared in step 3) ) And 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.240 g, 1.006 mmol) were mixed with tetrahydrofuran (10 mL) and irradiated with microwaves and heated at 150 ° C. for 30 minutes. Thereafter, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 50%) to give the title compound (0.096 g, 33.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.3 Hz), 7.44-7.31 (m, 5H), 7.07 (ddd, 2H, J = 60.8, 5.1, 4.6 Hz), 4.94 ( s, 2H), 2.18 (ddd, 1H, J = 11.4, 7.3, 3.1 Hz), 1.74-1.48 (m, 7H), 1.32-1.08 (m, 1H), 1.08-0.40 (m, 2H); LRMS (ES) m / z 430.3 (M ⁺ +1).

Example 4: Synthesis of Compound 11107, N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) benzamide

[Step 1] Synthesis of methyl 4-((N-phenylbenzamido) methyl) benzoate

Benzoyl in a solution of methyl 4-((phenylamino) methyl) benzoate (0.200 g, 0.829 mmol) and N, N-diisopropylethylamine (0.290 mL, 1.658 mmol) in methylene chloride (10 mL) at room temperature Chloride (0.175 g, 1.243 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.264 g, 92.2%) as a white solid.

[Step 2] Synthesis of N- (4- (hydrazinecarbonyl) benzyl) -N-phenylbenzamide

Methyl 4-((N-phenylbenzamido) methyl) benzoate (0.264 g, 0.764 mmol) and hydrazine hydrate (0.722 mL, 15.287 mmol) prepared in step 1 were mixed with ethanol (10 mL) and irradiated with microwaves. After heating at 120 ° C. for 2 hours, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0% to 15%) to give the title compound (0.222 g, 84.1%) as a white foamy solid.

[Step 3] Synthesis of N-phenyl-N- (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) benzamide

N- (4- (hydrazinecarbonyl) benzyl) -N-phenylbenzamide (0.364 g, 1.054 mmol) and triethylamine (0.292 mL, 2.108 mmol) prepared in step 2 were methylene chloride (10 mL) at room temperature. To the solution dissolved in trifluoroacetic anhydride (0.178 mL, 1.265 mmol) was added and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.450 g, 96.7%, white foamy solid).

[Step 4] Synthesis of Compound 11107

N-phenyl-N- (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) benzamide (0.450 g, 1.019 mmol) prepared in step 3 and 1- Methoxy-N-triethylammoniosulfonyl-methaneimite (Burgess reagent, 0.364 g, 1.529 mmol) was mixed with tetrahydrofuran (10 mL), irradiated with microwaves, heated at 150 ° C. for 30 minutes, and then the temperature was increased. The reaction was terminated by lowering to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.250 g, 57.9%) as a pale yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, 2H, J = 8.3 Hz), 7.54 (t, 2H, J = 9.9 Hz), 7.38-7.31 (m, 2H), 7.26-7.06 (m, 6H), 6.95 (dd, 2H, J = 10.5, 9.1 Hz), 5.23 (s, 2H); LRMS (ES) m / z 430.3 (M ⁺ +1)

Example 5: Synthesis of Compound 11108, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylisonicotinamide

N- (4- (hydrazinecarbonyl) benzyl) -N-phenylisonicotinamide (0.200 g, 0.577 mmol) prepared in step 3 of Example 1, 2,2-difluoroacetic anhydride (0.075 mL, 0.693 mmol) and triethylamine (0.160 mL, 1.155 mmol) in N, N-dimethylformamide (10 mL) at room temperature were stirred at 80 ° C. for 1 hour, and then the temperature was lowered to room temperature to terminate the reaction. It was. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.158 g, 67.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (d, 2H, J = 4.5 Hz), 8.06 (d, 2H, J = 8.2 Hz), 7.47 (d, 2H, J = 8.1 Hz), 7.19 (d , 5H, J = 5.1 Hz), 7.02 (d, 1H, J = 15.5 Hz), 6.90 (d, 3H, J = 5.8 Hz), 5.19 (s, 2H); LRMS (ES) m / z 407.3 (M ⁺ +1).

Example 6: Synthesis of Compound 11109, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenyliso Nicotinamide

[Step 1] Synthesis of Methyl 3-fluoro-4-((N-phenylisonicotinamido) methyl) benzoate

Methyl 3-fluoro-4-((phenylamino) methyl) benzoate (0.640 g, 2.468 mmol) and N, N-diisopropylethylamine (0.638 g, 4.937 mmol) were methylene chloride (10 mL) at room temperature. Isonicotin oil chloride hydrochloride (0.879 g, 4.937 mmol) was added to the solution, which was stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.840 g, 93.4%) as a yellow foamy solid.

[Step 2] Synthesis of N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N-phenylisonicotinamide

Methyl 3-fluoro-4-((N-phenylisonicotinamido) methyl) benzoate (0.840 g, 2.305 mmol) and hydrazine hydrate (2.177 mL, 46.106 mmol) prepared in step 1 were diluted with ethanol (10 mL). The mixture was heated in a microwave, irradiated with microwaves, heated at 120 ° C. for 2 hours, and the reaction was terminated by lowering the temperature to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0% to 15%) to give the title compound (0.814 g, 96.9%) as a white solid.

[Step 3] Synthesis of Compound 11109

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N-phenylisonicotinamide (0.100 g, 0.274 mmol) and triethylamine (0.076 mL, 0.549 mmol) prepared in step 2 were prepared at room temperature. Trifluoroacetic anhydride (0.046 mL, 0.329 mmol) was added to a solution dissolved in N, N-dimethylformamide (10 mL), stirred at 80 ° C. for 1 hour, and the reaction was terminated by lowering the temperature to room temperature. . Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / methylene chloride = 0% to 15%) to give the title compound (0.060 g, 49.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.49 (s, 2H), 7.89 (dd, 1H, J = 8.0, 1.4 Hz), 7.79-7.64 (m, 2H), 7.25 (d, 1H, J = 9.0 Hz), 7.29-7.03 (m, 5H), 7.03-6.89 (m, 2H), 5.27 (s, 2H); LRMS (ES) m / z 443.2 (M ⁺ +1).

Example 7: Synthesis of Compound 11110, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenyliso Nicotinamide

[Step 1] Synthesis of N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N-phenylisonicotinamide

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N-phenylisonicotinamide (0.100 g, 0.274 mmol) and triethylamine (0.076 mL, 0.549 mmol) prepared in Step 2 of Example 6 ) Was added to a solution of methylene chloride (10 mL) at room temperature, 2,2-difluoroacetic anhydride (0.057 g, 0.329 mmol) was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.120 g, 98.8%, colorless oil).

[Step 2] Synthesis of Compound 11110

N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N-phenylisonicotinamide (0.120 g, 0.271 mmol) prepared in step 1 ) And 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.097 g, 0.407 mmol) were mixed in tetrahydrofuran (10 mL) and irradiated with microwaves and heated at 150 ° C. for 30 minutes. Thereafter, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.027 g, 23.5%) as a pale yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, 2H, J = 5.5 Hz), 7.91 (dd, 1H, J = 8.0, 1.5 Hz), 7.90-7.57 (m, 2H), 7.29-7.07 ( m, 5H), 6.95 (ddd, 3H, J = 64.6, 48.3, 41.3 Hz), 5.27 (d, 2H, J = 14.0 Hz); LRMS (ES) m / z 425.3 (M ⁺ +1).

Example 8 Synthesis of Compound 11134, tert-butyl 3- (phenyl (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) carbamoyl) azetidine -1-carboxylate

[Step 1] Synthesis of tert-butyl 3- (phenylcarbamoyl) azetidine-1-carboxylate

Aniline (1.961 mL, 21.475 mmol), 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid (4.321 g, 21.475 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) (6.175 g, 32.213 mmol), 1H-benzo [d] [1,2,3] triazol-1-ol (HOBt) (4.353 g, 32.213 mmol) and N, N-diisopropylethylamine (5.703 mL, 32.213 mmol) dissolved in methylene chloride (150 mL) at room temperature was stirred at the same temperature for 12 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 120 g cartridge; ethyl acetate / hexane = 5% to 50%) to give the title compound (4.880 g, 82.2%) as a white solid.

[Step 2] Synthesis of tert-butyl 3-((4- (methoxycarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate

The tert-butyl 3- (phenylcarbamoyl) azetidine-1-carboxylate (1.000 g, 3.619 mmol) prepared in step 1 was dissolved in tetrahydrofuran (70 mL) and sodium hydride ( 60.00%, 0.289 g, 7.237 mmol) was added slowly and stirred for 20 minutes, after which methyl 4- (bromomethyl) benzoate (0.829 g, 3.619 mmol) was added and stirred at 45 ° C. for 12 hours for further temperature After lowering to room temperature, water (10 mL) was added to the reaction mixture at 0 ° C. and stirred for 5 minutes to terminate the reaction. Water was added to the reaction mixture, followed by extraction with ethyl acetate, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 120 g cartridge; ethyl acetate / hexane = 5% to 50%) to give the title compound (1.200 g, 78.1%) in the form of a colorless oil.

[Step 3] Synthesis of tert-butyl 3-((4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate

Tert-butyl 3-((4- (methoxycarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate (1.500 g, 3.534 mmol) prepared in step 2 and hydrazine monohydrate (3.435 mL, 70.671 mmol) was mixed with ethanol (15 mL) at room temperature and microwave-heated at 120 ° C. for 1 hour, and then the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was poured into water to remove the solvent under reduced pressure, and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (1.400 g, 93.3%, white solid).

[Step 4] Synthesis of tert-butyl 3- (phenyl (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) carbamoyl) azetidine-1-carboxylate

Tert-butyl 3-((4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate (1.800 g, 4.240 mmol) and triethylamine (0.710 mL, 5.088) prepared in step 3 mmol) was added to a solution of N, N-dimethylformamide (30 mL) at room temperature, trifluoroacetic anhydride (0.649 mL, 4.664 mmol) was added and stirred at 90 ° C. for 12 hours, and then the temperature was brought to room temperature. Lowered to complete the reaction. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 5% to 60%) to give the title compound (1.500 g, 68.0%) as a white solid.

[Step 5] Synthesis of Compound 11134

Tert-butyl 3- (phenyl (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) carbamoyl) azetidine-1-carboxylate prepared in step 4 1.500 g, 2.882 mmol) and a mixture of 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 1.030 g, 4.323 mmol) in tetrahydrofuran (15 mL) at room temperature were irradiated with microwaves. After heating at 150 ° C. for 30 minutes, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 5% to 30%) to give the title compound (1.200 g, 82.9%) as a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.2 Hz), 7.44-7.31 (m, 5H), 6.97-6.86 (m, 2H), 4.97 (s, 2H), 4.11 ( dd, 2H, J = 9.9, 4.1 Hz), 3.65 (dd, 2H, J = 11.2, 5.8 Hz), 3.34-3.14 (m, 1H), 1.40 (s, 9H); LRMS (ES) m / z 403.4 (M ⁺ -100).

Example 9 Synthesis of Compound 11135, tert-Butyl 4- (phenyl (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) carbamoyl) piperi Dean-1-carboxylate

[Step 1] Synthesis of tert-butyl 4- (phenylcarbamoyl) piperidine-1-carboxylate

Aniline (1.961 mL, 21.475 mmol), 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (4.924 g, 21.475 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodii Mede (EDC) (6.175 g, 32.213 mmol), 1H-benzo [d] [1,2,3] triazole-1-ol (HOBt) (4.353 g, 32.213 mmol) and N, N-diisopropylethyl A solution of amine (5.703 mL, 32.213 mmol) in methylene chloride (150 mL) at room temperature was stirred at the same temperature for 12 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 120 g cartridge; ethyl acetate / hexane = 5% to 50%) to give the title compound (5.040 g, 77.1%) as a white solid.

[Step 2] Synthesis of tert-butyl 4-((4- (methoxycarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate

The tert-butyl 4- (phenylcarbamoyl) piperidine-1-carboxylate (1.000 g, 3.285 mmol) prepared in step 1 was dissolved in tetrahydrofuran (70 mL) and sodium hydride while maintaining the temperature at 0 ° C. (60.00%, 0.263 g, 6.571 mmol) was added slowly and stirred for 20 minutes, followed by addition of methyl 4- (bromomethyl) benzoate (0.753 g, 3.285 mmol) and further stirring at 45 ° C. for 12 hours After lowering to room temperature, water (10 mL) was added to the reaction mixture at 0 ° C. and stirred for 5 minutes to terminate the reaction. Water was added to the reaction mixture, followed by extraction with ethyl acetate, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 120 g cartridge; ethyl acetate / hexane = 5% to 50%) to give the title compound (1.300 g, 87.4%) in the form of a colorless oil.

[Step 3] Synthesis of tert-butyl 4-((4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate

Tert-butyl 4-((4- (methoxycarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate (1.500 g, 3.315 mmol) and hydrazine monohydrate (3.319 g) prepared in step 2 , 66.291 mmol) in ethanol (15 mL) at room temperature was irradiated with microwaves and heated at 120 ° C. for 1 hour, and the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was poured into water to remove the solvent under reduced pressure, and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (1.400 g, 93.3%, white solid).

[Step 4] tert-butyl 4- (phenyl (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) carbamoyl) piperidine-1-carboxylate synthesis

Tert-butyl 4-((4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate (1.800 g, 3.977 mmol) prepared in step 3 and triethylamine (0.666 mL, 4.773 mmol) was added trifluoroacetic anhydride (0.609 mL, 4.375 mmol) to a solution of N, N-dimethylformamide (30 mL) at room temperature and stirred at 90 ° C. for 12 hours. Lowered to terminate the reaction. Saturated aqueous ammonium chloride solution was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 5% to 60%) to give the title compound (1.600 g, 73.3%) as a white solid.

[Step 5] Synthesis of Compound 11135

Tert-butyl 4- (phenyl (4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) carbamoyl) piperidine-1-carboxylate prepared in step 4 (1.600 g, 2.917 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 1.043 g, 4.375 mmol) were mixed in tetrahydrofuran (15 mL) at room temperature with microwave. After irradiation and heating at 150 ° C. for 30 minutes, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 5% to 30%) to give the title compound (1.400 g, 90.5%) as a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 8.03 (d, 2H, J = 8.0 Hz), 7.43-7.32 (m, 5H), 7.00 (d, 2H, J = 7.1 Hz), 4.96 (d, 2H, J = 20.2 Hz), 4.15-3.93 (m, 2H), 2.45 (s, 2H), 2.34 (t, 1H, J = 11.3 Hz), 1.77 (qd, 2H, J = 12.8, 4.0 Hz), 1.60 ( d, 2H, J = 12.7 Hz), 1.44 (s, 9H); LRMS (ES) m / z 531.4 (M ⁺ +1).

Example 10 Synthesis of Compound 11136, N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-car Voxamide Hydrochloride

Tert-Butyl 3- (phenyl (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) carbamoyl) azetidin-1- prepared in Example 8 Carboxylate (1.100 g, 2.189 mmol) was dissolved in dichloromethane (50 mL) and hydrochloric acid (4.00 M solution in dioxane, 2.736 mL, 10.945 mmol) was added at 0 ° C. and stirred at room temperature for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was suspended by pouring diethyl ether (50 mL) into the concentrate, filtered, and the resulting solid was washed with diethyl ether and dried to give the title compound (0.920 g, 95.8%). Obtained in white solid form.

¹ H NMR (700 MHz, CDCl ₃ + MeOD) δ 7.96 (dd, 2H, J = 45.0, 36.1 Hz), 7.35 (ddd, 5H, J = 40.2, 37.9, 10.0 Hz), 6.99 (d, 2H, J = 77.6 Hz), 5.12-4.80 ( m, 1H), 4.33 (s, 2H), 3.78 (d, 2H, J = 25.5 Hz), 3.30 (d, 1H, J = 120.8 Hz), 2.37 (s, 2H); LRMS (ES) m / z 403.0 (M ⁺ +1).

Example 11: Synthesis of Compound 11137, N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4- Carboxamide Hydrochloride

Tert-butyl 4- (phenyl (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) carbamoyl) piperidine-1 prepared in Example 9 Carboxylate (1.300 g, 2.450 mmol) was dissolved in dichloromethane (50 mL) and hydrochloric acid (4.00 M solution in dioxane, 3.063 mL, 12.251 mmol) was added at 0 ° C. and stirred at room temperature for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was suspended by pouring diethyl ether (50 mL) into the concentrate, filtered and the resulting solid was washed with diethyl ether and dried to give the title compound (1.080 g, 94.4%). Obtained in white solid form.

¹ H NMR (700 MHz, CDCl ₃ + MeOD) δ 7.91 (dd, 2H, J = 103.5, 50.3 Hz), 7.72-7.19 (m, 5H), 6.95 (s, 2H), 5.24-4.68 (m, 2H), 4.03-3.27 (m, 2H ), 3.04-2.64 (m, 2H), 2.49 (s, 2H), 2.09 (s, 2H), 1.78 (d, 2H, J = 93.2 Hz); LRMS (ES) m / z 431.4 (M ⁺ +1).

Example 12 Synthesis of Compound 11138, 1-Methyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine -3-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-carboxamide hydro prepared in Example 10 In a solution of chloride (0.100 g, 0.228 mmol) and formaldehyde (37.00% solution in water, 0.025 mL, 0.342 mmol) in dichloromethane (10 mL) at room temperature, sodium triacetoxyborohydride (0.072 g, 0.342 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.038 g, 40.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.2 Hz), 7.52-7.30 (m, 6H), 6.90 (dd, 2H, J = 6.5, 2.8 Hz), 4.92 (d, 2H, J = 19.3 Hz), 3.51-3.14 (m, 5H), 2.35 (s, 3H); LRMS (ES) m / z 417.3 (M ⁺ +1).

Example 13: Synthesis of Compound 11139, 1-ethyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine -3-carboxamide

[Step 1] Synthesis of Compound 11139

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-carboxamide hydro prepared in Example 10 To a solution of chloride (0.100 g, 0.228 mmol) and acetaldehyde (0.019 mL, 0.342 mmol) in dichloromethane (10 mL) at room temperature was added sodium triacetoxyborohydride (0.072 g, 0.342 mmol). Stir at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.042 g, 42.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07-7.97 (m, 2H), 7.34 (dt, 5H, J = 22.3, 14.0 Hz), 6.95-6.83 (m, 2H), 4.92 (d, 2H, J = 19.5 Hz), 3.55-3.08 (m, 5H), 2.58 (q, 2H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.2 Hz); LRMS (ES) m / z 431.3 (M ⁺ +1).

Example 14 Synthesis of Compound 11140, 1-Methyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperi Din-4-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 Sodium triacetoxyborohydride (0.068 g) in a solution of hydrochloride (0.100 g, 0.214 mmol) and formaldehyde (37.00% solution in water, 0.024 mL, 0.321 mmol) in dichloromethane (10 mL) at room temperature , 0.321 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.072 g, 75.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.3 Hz), 7.43-7.30 (m, 5H), 6.97 (dd, 2H, J = 6.4, 3.2 Hz), 4.94 (s, 2H), 2.78 (d, 2H, J = 113.6 Hz), 2.16 (dd, 4H, J = 68.5, 23.5 Hz), 1.96 (dt, 3H, J = 20.3, 13.8 Hz), 1.73 (s, 2H); LRMS (ES) m / z 431.3 (M ⁺ +1).

Example 15 Synthesis of Compound 11141, 1-ethyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperi Din-4-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 Sodium triacetoxyborohydride (0.068 g, 0.321 mmol) was dissolved in a solution of hydrochloride (0.100 g, 0.214 mmol) and acetaldehyde (0.018 mL, 0.321 mmol) in dichloromethane (10 mL) at room temperature. It was added and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to afford the title compound (0.065 g, 66.2%) in the form of a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.3 Hz), 7.43-7.31 (m, 5H), 6.97 (dd, 2H, J = 6.6, 2.9 Hz), 4.94 (s, 2H), 3.04 (s, 2H), 2.40 (d, 3H, J = 75.4 Hz), 2.02-1.66 (m, 6H), 1.15 (dd, 3H, J = 32.3, 25.8 Hz); LRMS (ES) m / z 459.34 (M ⁺ +1)

Example 16: Synthesis of Compound 11142, 1-Isopropyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) ase Tidine-3-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-carboxamide hydro prepared in Example 10 Sodium triacetoxyborohydride (0.072 g, 0.342 mmol) was added to a solution of chloride (0.100 g, 0.228 mmol) and acetone (0.025 mL, 0.342 mmol) in dichloromethane (10 mL) at room temperature. Stir at temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.056 g, 55.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.2 Hz), 7.42-7.28 (m, 5H), 6.91 (dd, 2H, J = 6.4, 3.1 Hz), 4.94 (s, 2H), 3.31 (d, 5H, J = 21.1 Hz), 2.50 (s, 1H), 0.94 (d, 6H, J = 6.1 Hz); LRMS (ES) m / z 445.3 (M ⁺ +1).

Example 17 Synthesis of Compound 11143, 1-Isopropyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) pi Ferridine-4-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 To a solution of hydrochloride (0.100 g, 0.214 mmol) and acetone (0.024 mL, 0.321 mmol) in dichloromethane (10 mL) at room temperature was added sodium triacetoxyborohydride (0.068 g, 0.321 mmol) Stir at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.021 g, 20.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, 2H, J = 8.3 Hz), 7.36 (dd, 5H, J = 7.4, 4.2 Hz), 6.95 (dd, 2H, J = 6.5, 3.1 Hz) , 4.92 (s, 2H), 3.37 (d, 3H, J = 63.0 Hz), 2.75 (d, 3H, J = 67.4 Hz), 2.22 (s, 1H), 1.96 (s, 2H, J = 30.4 Hz) , 1.25 (s, 6H, J = 169.3 Hz); LRMS (ES) m / z 473.3 (M ⁺ +1).

Example 18 Synthesis of Compound 11157, N-phenyl-1-propionyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) ase Tidine-3-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-carboxamide hydro prepared in Example 10 Propionyl chloride (0.018 mL, 0.201 mmol) in a solution of chloride (0.080 g, 0.182 mmol) and N, N-diisopropylethylamine (0.063 mL, 0.365 mmol) in dichloromethane (10 mL) at room temperature. Was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.008 g, 9.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, 2H, J = 8.2 Hz), 7.45-7.29 (m, 6H), 6.92 (dd, 2H, J = 6.5, 2.8 Hz), 4.98 (s, 2H), 4.37-4.08 (m, 2H), 3.79 (d, 2H, J = 6.7 Hz), 3.30 (ddd, 1H, J = 15.1, 8.8, 6.4 Hz), 2.15-1.94 (m, 3H), 1.25 (s, 1H, J = 20.0 Hz), 1.09 (t, 3H, J = 7.5 Hz); LRMS (ES) m / z 459.3 (M ⁺ +1).

Example 19 Synthesis of Compound 11158, 1-isobutyryl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) Azetidine-3-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-carboxamide hydro prepared in Example 10 Isobutyryl chloride (0.021 mL, 0.201 mmol) in a solution of chloride (0.080 g, 0.182 mmol) and N, N-diisopropylethylamine (0.063 mL, 0.365 mmol) in dichloromethane (10 mL) at room temperature. ) Was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.025 g, 29.0%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, 2H, J = 8.3 Hz), 7.45-7.28 (m, 5H), 6.92 (dd, 2H, J = 6.3, 3.2 Hz), 5.04-4.87 ( m, 2H), 4.53-4.16 (m, 1H), 3.95-3.59 (m, 2H), 3.36 3.20 (m, 1H), 2.39 (td, 2H, J = 13.6, 6.8 Hz), 1.07 (dd, 6H , J = 16.3, 6.8 Hz); LRMS (ES) m / z 473.3 (M ⁺ +1).

Example 20 Synthesis of Compound 11159, N-phenyl-1- (2,2,2-trifluoroacetyl) -N- (4- (5- (trifluoromethyl) -1,3,4-oxa Diazol-2-yl) benzyl) azetidine-3-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-carboxamide hydro prepared in Example 10 2,2,2-trifluoroacetic acid in a solution of chloride (0.080 g, 0.182 mmol) and N, N-diisopropylethylamine (0.063 mL, 0.365 mmol) in dichloromethane (10 mL) at room temperature Anhydrous (0.028 mL, 0.201 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.013 g, 14.3%) as colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, 2H, J = 8.2 Hz), 7.44-7.31 (m, 5H), 6.96-6.83 (m, 2H), 4.97 (t, 2H, J = 8.2 Hz), 4.72-4.62 (m, 1H), 4.14 (dt, 2H, J = 14.4, 8.2 Hz), 3.89-3.76 (m, 1H), 3.50-3.36 (m, 1H); LRMS (ES) m / z 499.3 (M ⁺ +1).

Example 21 Synthesis of Compound 11160, 1- (methylsulfonyl) -N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) Benzyl) azetidine-3-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-carboxamide hydro prepared in Example 10 Methanesulfonyl chloride (0.016 mL, 0.201 mmol) in a solution of chloride (0.080 g, 0.182 mmol) and N, N-diisopropylethylamine (0.064 mL, 0.365 mmol) in dichloromethane (10 mL) at room temperature. ) Was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.018 g, 20.6%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08-7.98 (m, 2H), 7.43-7.31 (m, 5H), 6.91 (ddd, 2H, J = 5.5, 4.6, 2.9 Hz), 4.96 (s, 2H ), 4.12 (dd, 2H, J = 15.2, 7.3 Hz), 3.72-3.62 (m, 2H), 3.38-3.26 (m, 1H), 2.89 (d, 3H, J = 4.0 Hz); LRMS (ES) m / z 481.2 (M ⁺ +1).

Example 22 Synthesis of Compound 11161, 1-acetyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperi Din-4-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 Acetyl chloride (0.013 mL, 0.188 mmol) in a solution of hydrochloride (0.080 g, 0.171 mmol) and N, N-diisopropylethylamine (0.059 mL, 0.343 mmol) in dichloromethane (10 mL) at room temperature Was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.052 g, 64.2%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.3 Hz), 7.37 (dd, 5H, J = 5.4, 3.0 Hz), 6.99 (dd, 2H, J = 6.6, 2.9 Hz) , 4.94 (s, 2H), 4.51 (s, 1H), 3.77 (s, 1H), 2.80 (s, 1H), 2.38 (ddd, 2H, J = 30.5, 20.3, 9.3 Hz), 2.04 (s, 3H , J = 9.5, 4.9 Hz), 1.88-1.53 (m, 4H); LRMS (ES) m / z 473.3 (M ⁺ +1).

Example 23 Synthesis of Compound 11162, N-phenyl-1-propionyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) pi Ferridine-4-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 Propionyl chloride (0.016 mL, 0.188 mmol) in a solution of hydrochloride (0.080 g, 0.171 mmol) and N, N-diisopropylethylamine (0.059 mL, 0.343 mmol) in dichloromethane (10 mL) at room temperature. ) Was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.061 g, 73.2%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.0 Hz), 7.37 (dd, 5H, J = 5.0, 3.0 Hz), 6.99 (dd, 2H, J = 6.2, 2.6 Hz) , 4.94 (s, 2H), 4.51 (s, 1H), 3.85 (s, 1H), 2.36 (ddd, 4H, J = 21.9, 14.8, 9.1 Hz), 1.90 1.52 (m, 5H), 1.12 (t, 3H, J = 7.5 Hz); LRMS (ES) m / z 487.4 (M ⁺ +1).

Example 24 Synthesis of Compound 11163, 1-isobutyryl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) Piperidine-4-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 Isobutyryl chloride (0.020 mL, 0.188) in a solution of hydrochloride (0.080 g, 0.171 mmol) and N, N-diisopropylethylamine (0.059 mL, 0.343 mmol) in dichloromethane (10 mL) at room temperature mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.064 g, 74.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.3 Hz), 7.37 (dd, 5H, J = 5.3, 3.1 Hz), 6.99 (dd, 2H, J = 6.2, 3.2 Hz) , 4.94 (s, 2H), 2.74 (dt, 2H, J = 13.4, 6.7 Hz), 2.48-2.26 (m, 2H), 1.90-1.49 (m, 6H), 1.10 (t, 6H, J = 11.3 Hz ); LRMS (ES) m / z 501.3 (M ⁺ +1).

Example 25 Synthesis of Compound 11164, N-phenyl-1- (2,2,2-trifluoroacetyl) -N- (4- (5- (trifluoromethyl) -1,3,4-oxa Diazol-2-yl) benzyl) piperidine-4-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 2,2,2-trifluoro in a solution of hydrochloride (0.080 g, 0.171 mmol) and N, N-diisopropylethylamine (0.059 mL, 0.343 mmol) in dichloromethane (10 mL) at room temperature Acetic anhydride (0.027 mL, 0.188 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.061 g, 67.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, 2H, J = 8.2 Hz), 7.38 (t, 5H, J = 7.1 Hz), 7.05-6.87 (m, 2H), 4.94 (q, 2H, J = 14.5 Hz), 4.42 (d, 1H, J = 13.2 Hz), 3.97 (d, 1H, J = 14.3 Hz), 2.93 (t, 1H, J = 13.1 Hz), 2.62 (t, 1H, J = 12.0 Hz), 2.50 (dd, 1H, J = 12.5, 8.5 Hz), 1.89 (dd, 2H, J = 24.8, 13.1 Hz), 1.72 (d, 2H, J = 14.0 Hz); LRMS (ES) m / z 527.3 (M ⁺ +1).

Example 26 Synthesis of Compound 11165, 1- (methylsulfonyl) -N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) Benzyl) piperidine-4-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 Methanesulfonyl chloride (0.015 mL, 0.188) in a solution of hydrochloride (0.080 g, 0.171 mmol) and N, N-diisopropylethylamine (0.060 mL, 0.343 mmol) in dichloromethane (10 mL) at room temperature mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.070 g, 80.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, 2H, J = 8.1 Hz), 7.37 (dd, 5H, J = 5.3, 2.8 Hz), 6.98 (dd, 2H, J = 6.3, 2.7 Hz) , 4.94 (s, 2H), 3.80-3.62 (m, 2H), 2.72 (s, 3H), 2.51 (dd, 2H, J = 16.4, 7.1 Hz), 2.38 2.22 (m, 1H), 2.02 1.84 (m , 2H), 1.78 1.66 (m, 2H); LRMS (ES) m / z 509.2 (M ⁺ +1).

Example 27 Synthesis of Compound 11166, 1-benzyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperi Din-4-carboxamide

[Step 1] Synthesis of Compound 11166

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) piperidine-4-carboxamide prepared in Example 11 (Bromomethyl) benzene (0.024 mL) in a solution of hydrochloride (0.080 g, 0.171 mmol) and N, N-diisopropylethylamine (0.059 mL, 0.343 mmol) in dichloromethane (10 mL) at room temperature. , 0.206 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.060 g, 67.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 (d, 2H, J = 8.0 Hz), 7.44-7.24 (m, 10H), 7.02-6.84 (m, 2H), 4.94 (s, 2H), 3.41 ( s, 2H), 2.83 (s, 2H), 2.17 (s, 1H), 1.93 (d, 2H, J = 10.8 Hz), 1.64 (d, 5H, J = 36.5 Hz); LRMS (ES) m / z 521.4 (M ⁺ +1).

Example 28 Synthesis of Compound 11187, N1-acetyl-N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine -3-carboxamide

N-phenyl-N- (4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) azetidine-3-carboxamide hydro prepared in Example 10 Acetyl chloride (0.014 mL, 0.201 mmol) was dissolved in a solution of chloride (0.080 g, 0.182 mmol) and N, N-diisopropylethylamine (0.063 mL, 0.365 mmol) in dichloromethane (10 mL) at room temperature. It was added and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate, 20 × 20 × 1 mm; 100% -ethylacetate solution / hexane = 100%) to concentrate the title compound (0.020 g, 24.7%) in the form of a colorless oil. Got it.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, 2H, J = 8.1 Hz), 7.44-7.28 (m, 5H), 6.91 (dd, 2H, J = 6.5, 2.4 Hz), 4.97 (s, 2H), 4.44 (s, 1H), 3.92 (dd, 3H, J = 107.3, 55.1 Hz), 3.29 (ddd, 1H, J = 15.2, 8.8, 6.3 Hz), 1.81 (d, 3H, J = 6.8 Hz ); LRMS (ES) m / z 445.3 (M ⁺ +1).

Example 29 Synthesis of Compound 11188, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N- (3 -Fluorophenyl) isonicotinamide

[Step 1] Synthesis of methyl 3-fluoro-4-(((3-fluorophenyl) amino) methyl) benzoate

3-fluoroaniline (0.200 g, 1.800 mmol), methyl 4- (bromomethyl) -3-fluorobenzoate (0.445 g, 1.800 mmol) and potassium carbonate (0.497 g, 3.600 mmol) were acetonite at room temperature. The solution dissolved in reel (15 mL) was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.324 g, 64.9%) in the form of a colorless oil.

[Step 2] Synthesis of methyl 3-fluoro-4-((N- (3-fluorophenyl) isonicotinamido) methyl) benzoate

Methyl 3-fluoro-4-(((3-fluorophenyl) amino) methyl) benzoate (0.320 g, 1.154 mmol) prepared in step 1, isonicotinyl chloride hydrochloride (0.247 g, 1.385 mmol) and A solution of N, N-diisopropylethylamine (0.398 mL, 2.308 mmol) in dichloromethane (10 mL) at room temperature was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.300 g, 68.0%) as a yellow foamy solid.

[Step 3] Synthesis of N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) isonicotinamide

Methyl 3-fluoro-4-((N- (3-fluorophenyl) isonicotinamido) methyl) benzoate (0.300 g, 0.785 mmol) and hydrazine hydrate (0.786 g, 15.692 mmol) prepared in step 2 The mixture was mixed with ethanol (20 mL) at room temperature and heated to reflux for 18 hours, and then lowered to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.250 g, 83.3%, yellow foamy solid).

[Step 4] N- (2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) -N- (3-fluorophenyl) isonicotin Synthesis of Amide

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) isonicotinamide (0.125 g, 0.327 mmol) prepared in step 3 and triethylamine (0.091 mL, 0.654 mmol) was added trifluoroacetic anhydride (0.055 mL, 0.392 mmol) to a solution dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.145 g, 92.7%, yellow foamy solid).

[Step 5] Synthesis of Compound 11188

N- (2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) -N- (3-fluorophenyl) iso prepared in step 4 Nicotinamide (0.160 g, 0.334 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimate (Burgess reagent, 0.120 g, 0.502 mmol) were mixed in tetrahydrofuran (10 mL) and irradiated with microwaves. After heating at 150 ° C. for 30 minutes, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.058 g, 37.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 (s, 2H), 7.91 (dd, 1H, J = 8.0, 1.5 Hz), 7.83-7.57 (m, 2H), 7.37-7.27 (m, 2H), 7.17 (dd, 1H, J = 8.1, 6.3 Hz), 6.94 (td, 1H, J = 8.1, 2.3 Hz), 6.78-6.62 (m, 2H), 5.23 (d, 2H, J = 20.2 Hz); LRMS (ES) m / z 461.3 (M ⁺ +1).

Example 30: Synthesis of Compound 11189, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) isonicotinamide

[Step 1] of N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N- (3-fluorophenyl) isonicotinamide synthesis

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) isonicotinamide (0.125 g, 0.327 mmol) and triethylamine prepared in step 3 of Example 29 To a solution of (0.091 mL, 0.654 mmol) in dichloromethane (10 mL) at room temperature, 2,2-difluoroacetic anhydride (0.043 mL, 0.392 mmol) was added and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.135 g, 89.7%, yellow foamy solid).

[Step 2] Synthesis of Compound 11189

N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N- (3-fluorophenyl) isonicotinamide prepared in step 1 (0.160 g, 0.348 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.124 g, 0.521 mmol) were mixed with tetrahydrofuran (10 mL) and irradiated with microwave at 150 ° C. After heating for 30 minutes at, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.089 g, 57.9%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 (d, 2H, J = 4.8 Hz), 7.91 (d, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 9.9 Hz), 7.68 (t , 1H, J = 7.6 Hz), 7.32 (d, 2H, J = 2.9 Hz), 7.17 (dd, 1H, J = 14.7, 7.3 Hz), 7.05-6.83 (m, 2H), 6.83 6.61 (m, 2H ), 5.33 5.12 (m, 2 H); LRMS (ES) m / z 442.9 (M ⁺ +1).

Example 31 Synthesis of Compound 11200, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -1-methyl- N-phenylpiperidine-4-carboxamide

[Step 1] Synthesis of tert-butyl 4-((2-fluoro-4- (methoxycarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate

The tert-butyl 4- (phenylcarbamoyl) piperidine-1-carboxylate (2.000 g, 6.571 mmol) prepared in step 1 of Example 9 was dissolved in tetrahydrofuran (80 mL) and the temperature was maintained at 0 ° C. Sodium hydride (60.00%, 0.526 g, 13.141 mmol) was added slowly and stirred for 20 minutes, then methyl 4- (bromomethyl) -3-fluorobenzoate (1.948 g, 7.885 mmol) was added and 50 After further stirring for 12 hours at ° C to lower the temperature to room temperature, water (20 mL) was added to the reaction mixture at 0 ° C and the reaction was terminated by stirring for 5 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 5% to 50%) to give the title compound (2.600 g, 84.1%) as a colorless oil.

[Step 2] Synthesis of tert-butyl 4-((2-fluoro-4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate

Tert-butyl 4-((2-fluoro-4- (methoxycarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate (2.500 g, 5.313 mmol) and hydrazine prepared in step 1 The mixture of monohydrate (5.154 mL, 106.261 mmol) in ethanol (100 mL) at room temperature was heated to reflux for 12 hours, then lowered to room temperature, and the reaction mixture was poured into water to remove the solvent under reduced pressure, followed by dichloromethane. Extracted with methane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (2.400 g, 96.0%, white solid).

[Step 3] tert-Butyl 4-((2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) (phenyl) carbamoyl) piperi Synthesis of Didine-1-carboxylate

Tert-butyl 4-((2-fluoro-4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate (1.200 g, 2.550 mmol) and triethyl prepared in step 2 To a solution of amine (0.427 mL, 3.060 mmol) in dichloromethane (50 mL) at room temperature was added trifluoroacetic anhydride (0.390 mL, 2.805 mmol) and stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (1.400 g, 96.9%, colorless oil).

[Step 4] tert-Butyl 4-((2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) (phenyl) carbamoyl) Synthesis of Piperidine-1-carboxylate

Tert-butyl 4-((2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) (phenyl) carbamoyl) blood prepared in step 3 Ferridine-1-carboxylate (1.400 g, 2.471 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.883 g, 3.707 mmol) were tetrahydrofuran (100 mL) at room temperature. ), The mixture was heated to reflux for 12 hours and then lowered to room temperature, the reaction mixture was removed from the solvent under reduced pressure, and the concentrate was purified by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 10%). 30%) to give the title compound (0.740 g, 54.6%) as a white solid.

[Step 5] N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpiperidine-4- Synthesis of Carboxamide Hydrochloride

Tert-butyl 4-((2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) (phenyl) carbamoyl prepared in step 4 To a solution of piperidine-1-carboxylate (0.740 g, 1.349 mmol) in dichloromethane (50 mL) at room temperature, hydrochloric acid (4.00 M solution in dioxane, 1.686 mL, 6.745 mmol) was added to the same temperature. Stirred for 12 h. After removing the solvent under reduced pressure, the reaction mixture was suspended by pouring diethyl ether (50 mL) into the concentrate, filtered and the resulting solid was washed with diethyl ether and dried to give the title compound (0.610 g, 93.3%). Obtained in white solid form.

[Step 6] Synthesis of Compound 11200

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpiperidine-4 prepared in step 5 -Carboxamide Hydrochloride (0.050 g, 0.103 mmol), Formaldehyde (37.00% solution in water, 0.012 mL, 0.155 mmol) and sodium triacetoxyborohydride (0.033 g, 0.155 mmol) at room temperature The solution dissolved in phosphorus (4 mL) was stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.020 g, 41.9). %) Was obtained in the form of a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.86 (d, 1H, J = 7.8 Hz), 7.72 (d, 1H, J = 9.4 Hz), 7.56 (t, 1H, J = 7.0 Hz), 7.36 (d , 3H, J = 12.4 Hz), 7.03 (t, 2H, J = 13.6 Hz), 5.01 (d, 2H, J = 22.8 Hz), 3.32-3.03 (m, 2H), 2.53-2.38 (m, 4H) , 2.03 (dd, 4H, J = 43.3, 40.1 Hz), 1.86 (d, 2H, J = 48.6 Hz); LRMS (ES) m / z 463.3 (M ⁺ +1).

Example 32 Synthesis of Compound 11201, 1-ethyl-N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl)- N-phenylpiperidine-4-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpi prepared in step 5 of Example 31. Ferridine-4-carboxamide hydrochloride (0.050 g, 0.103 mmol), acetaldehyde (0.009 mL, 0.155 mmol) and sodium triacetoxyborohydride (0.033 g, 0.155 mmol) were dichloromethane at room temperature. The solution dissolved in (4 mL) was stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.025 g, 50.9 %) Was obtained in the form of a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.85 (d, 1H, J = 6.8 Hz), 7.71 (d, 1H, J = 8.8 Hz), 7.53 (s, 1H), 7.36 (s, 3H), 7.01 (d, 2H, J = 26.5 Hz), 5.11-4.94 (m, 2H), 3.26 (s, 3H), 2.77 (s, 2H), 2.48 (s, 3H), 2.05 2.00 (m, 3H, J = 57.5 Hz), 1.22 (d, 3H, J = 5.3 Hz); LRMS (ES) m / z 477.3 (M ⁺ +1).

Example 33 Synthesis of Compound 11202, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -1-isopropyl -N-phenylpiperidine-4-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpi prepared in step 5 of Example 31. Ferridine-4-carboxamide hydrochloride (0.050 g, 0.103 mmol), acetone (0.011 mL, 0.155 mmol) and sodium triacetoxyborohydride (0.033 g, 0.155 mmol) were diluted with dichloromethane ( 4 mL) was stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.020 g, 39.5 %) Was obtained in the form of a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.86 (d, 1H, J = 7.9 Hz), 7.73 (d, 1H, J = 9.5 Hz), 7.55-7.48 (m, 1H), 7.40-7.33 (m, 3H), 7.05-6.98 (m, 2H), 5.02 (s, 2H), 3.40 (t, 3H, J = 58.2 Hz), 2.78 (d, 2H, J = 8.9 Hz), 2.60 (s, 1H), 2.11 (d, 2H, J = 36.1 Hz), 2.00 (d, 4H, J = 9.5 Hz), 1.30 (d, 4H, J = 5.9 Hz); LRMS (ES) m / z 491.0 (M ⁺ +1).

Example 34 Synthesis of Compound 11203, 1-acetyl-N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl)- N-phenylpiperidine-4-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpi prepared in step 5 of Example 31. Acetyl in a solution of ferridine-4-carboxamide hydrochloride (0.050 g, 0.103 mmol) and N, N-diisopropylethylamine (0.036 mL, 0.206 mmol) in dichloromethane (4 mL) at room temperature Chloride (0.008 mL, 0.113 mmol) was added and stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.032 g, 63.3%). ) Was obtained in the form of a colorless oil.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.87 (d, 1H, J = 7.9 Hz), 7.72 (d, 1H, J = 9.4 Hz), 7.62-7.55 (m, 1H), 7.39 (s, 3H) , 7.12-7.02 (m, 2H), 5.04 (s, 2H), 4.53 (s, 1H), 3.79 (s, 1H), 2.84 (s, 1H), 2.51-2.42 (m, 1H), 2.34 (s , 1H), 2.06 (t, 4H, J = 4.7 Hz), 1.78 (d, 3H, J = 69.3 Hz); LRMS (ES) m / z 491.1 (M ⁺ +1).

Example 35 Synthesis of Compound 11204, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenyl- 1-propionylpiperidine-4-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpi prepared in step 5 of Example 31. Pyridine-4-carboxamide hydrochloride (0.050 g, 0.103 mmol) and N, N-diisopropylethylamine (0.036 mL, 0.206 mmol) were dissolved in dichloromethane (4 mL) at room temperature. Onyl chloride (0.010 mL, 0.113 mmol) was added and stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 57.7%). ) Was obtained in the form of a colorless oil.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.87 (t, 1H, J = 6.2 Hz), 7.74-7.70 (m, 1H), 7.58 (d, 1H, J = 6.7 Hz), 7.39 (d, 3H, J = 4.5 Hz), 7.06 (s, 2H), 5.04 (s, 3H), 4.54 (s, 1H), 3.83 (s, 1H), 2.78 (s, 1H), 2.31 (s, 4H), 1.77 ( s, 2H, J = 67.0 Hz), 1.19 1.02 (m, 4H); LRMS (ES) m / z 505.3 (M ⁺ +1).

Example 36 Synthesis of Compound 11205, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -1-isobeauty Reel-N-phenylpiperidine-4-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpi prepared in step 5 of Example 31. Ferridine-4-carboxamide hydrochloride (0.050 g, 0.103 mmol) and N, N-diisopropylethylamine (0.036 mL, 0.206 mmol) were dissolved in dichloromethane (4 mL) at room temperature. Butyryl chloride (0.012 mL, 0.113 mmol) was added and stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 56.1%). ) Was obtained in the form of a colorless oil.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.87 (d, 1H, J = 8.0 Hz), 7.71 (t, 1H, J = 11.3 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.42-7.37 (m, 3H), 7.07 (d, 2H, J = 7.7 Hz), 5.00 (d, 2H, J = 39.7 Hz), 4.56 (s, 1H), 4.04 3.80 (m, 1H), 2.94-2.66 (m , 2H), 2.53-2.41 (m, 1H), 2.31 (dt, 1H, J = 45.9, 23.1 Hz), 1.76 (dd, 2H, J = 36.0, 30.1 Hz), 1.10 (d, 8H, J = 6.8 Hz); LRMS (ES) m / z 519.5 (M ⁺ +1).

Example 37 Synthesis of Compound 11206, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenyl- 1- (2,2,2-trifluoroacetyl) piperidine-4-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpi prepared in step 5 of Example 31. Tridine-4-carboxamide hydrochloride (0.050 g, 0.103 mmol) and N, N-diisopropylethylamine (0.036 mL, 0.206 mmol) were dissolved in dichloromethane (4 mL) at room temperature. Fluoroacetic anhydride (0.016 mL, 0.113 mmol) was added and stirred at the same temperature for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 53.4%). ) Was obtained in the form of a colorless oil.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.87 (d, 1H, J = 8.0 Hz), 7.73 (d, 1H, J = 9.6 Hz), 7.57 (t, 1H, J = 7.4 Hz), 7.41 (d , 3H, J = 5.4 Hz), 7.07 (d, 2H, J = 6.9 Hz), 5.10-4.98 (m, 2H), 4.43 (d, 1H, J = 13.4 Hz), 3.98 (d, 1H, J = 13.8 Hz), 2.96 (t, 1H, J = 12.8 Hz), 2.74-2.58 (m, 1H), 2.54 (t, 1H, J = 10.5 Hz), 1.96-1.81 (m, 2H), 1.75 (d, 2H, J = 13.0 Hz); LRMS (ES) m / z 545.4 (M ⁺ +1).

Example 38 Synthesis of Compound 11207, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -1- (methyl Sulfonyl) -N-phenylpiperidine-4-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpi prepared in step 5 of Example 31. Pyridine-4-carboxamide hydrochloride (0.050 g, 0.103 mmol) and N, N-diisopropylethylamine (0.036 mL, 0.206 mmol) were dissolved in a solution of dichloromethane (4 mL) at room temperature. Insulfonyl chloride (0.009 mL, 0.113 mmol) was added and stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 55.3% ) Was obtained in the form of a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.87 (d, 1H, J = 7.8 Hz), 7.73 (d, 1H, J = 9.4 Hz), 7.58 (t, 1H, J = 6.4 Hz), 7.39 (s , 3H), 7.06 (d, 2H, J = 5.7 Hz), 5.04 (s, 2H), 3.74 (d, 2H, J = 10.1 Hz), 2.74 (d, 3H, J = 2.1 Hz), 2.54 (t , 2H, J = 11.7 Hz), 2.36 (dd, 1H, J = 10.1, 7.7 Hz), 1.95 (dd, 2H, J = 23.6, 11.6 Hz), 1.75 (d, 2H, J = 13.2 Hz); LRMS (ES) m / z 527.3 (M ⁺ +1).

Example 39: Synthesis of Compound 11208, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-methyl- N-phenylpiperidine-4-carboxamide

[Step 1] tert-Butyl 4-((4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) (phenyl) carbamoyl) piperidine- Synthesis of 1-carboxylate

Tert-Butyl 4-((2-fluoro-4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) piperidine-1-carboxylate (1.200 g, 2.550 mmol) prepared in step 2 of Example 31 ) And triethylamine (0.427 mL, 3.060 mmol) in a solution of dichloromethane (50 mL) at room temperature were added difluoroacetic anhydride (0.349 mL, 2.805 mmol) and stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (1.350 g, 96.5%, colorless oil).

[Step 2] tert-Butyl 4-((4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) (phenyl) carbamoyl) Synthesis of Piperidine-1-carboxylate

Tert-Butyl 4-((4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) (phenyl) carbamoyl) piperidine prepared in step 1 -1-carboxylate (1.350 g, 2.461 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.880 g, 3.691 mmol) were added to tetrahydrofuran (100 mL) at room temperature. The mixed mixture was heated to reflux for 12 hours, then lowered to room temperature, the reaction mixture was removed from the solvent under reduced pressure, and the concentrate was then purified by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 10% to 30%). ) And purified to give the title compound (0.800 g, 61.3%) as a white solid.

[Step 3] N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpiperidine-4- Synthesis of Carboxamide Hydrochloride

Tert-butyl 4-((4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) (phenyl) carbamoyl prepared in step 2 To a solution of piperidine-1-carboxylate (0.800 g, 1.508 mmol) in dichloromethane (50 mL) at room temperature, hydrochloric acid (4.00 M solution in dioxane, 1.885 mL, 7.539 mmol) was added at the same temperature. Stirred for 12 h. After removing the solvent under reduced pressure, the reaction mixture was suspended by pouring diethyl ether (50 mL) into the concentrate, filtered and the solid obtained was washed with diethyl ether and dried to give the title compound (0.660 g, 93.7%). Obtained in white solid form.

[Step 4] Synthesis of Compound 11208

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpiperidine-4 prepared in step 3 -Carboxamide Hydrochloride (0.050 g, 0.107 mmol), Formaldehyde (37.00% solution in water, 0.012 mL, 0.161 mmol) and Sodium triacetoxyborohydride (0.034 g, 0.161 mmol) at room temperature The solution dissolved in phosphorus (4 mL) was stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.022 g, 46.2). %) Was obtained in the form of a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.86 (t, 1H, J = 13.4 Hz), 7.72 (d, 1H, J = 9.7 Hz), 7.55 (t, 1H, J = 7.5 Hz), 7.41-7.33 (m, 3H), 7.09-7.02 (m, 2H), 6.92 (t, 1H, J = 51.7 Hz), 5.07-4.94 (m, 2H), 3.16-3.02 (m, 2H), 2.38 (s, 1H ), 2.24 (s, 3H), 1.97 (d, 3H, J = 9.6 Hz), 1.81 (d, 3H, J = 9.7 Hz); LRMS (ES) m / z 445.3 (M ⁺ +1).

Example 40 Synthesis of Compound 11209, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-ethyl- N-phenylpiperidine-4-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpi prepared in step 3 of Example 39 Ferridine-4-carboxamide hydrochloride (0.050 g, 0.107 mmol), acetaldehyde (0.009 mL, 0.161 mmol) and sodium triacetoxyborohydride (0.034 g, 0.161 mmol) were dichloromethane at room temperature. The solution dissolved in (4 mL) was stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.025 g, 50.9 %) Was obtained in the form of a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.86 (d, 1H, J = 6.0 Hz), 7.73 (d, 1H, J = 6.7 Hz), 7.52 (s, 1H), 7.37 (s, 3H), 7.03 (s, 2H), 6.88 (d, 1H, J = 51.6 Hz), 5.02 (s, 2H), 3.48 (d, 2H, J = 5.4 Hz), 3.25 (s, 3H), 2.77 (s, 3H) , 2.50 (s, 2 H), 1.25 (s, 4 H); LRMS (ES) m / z 459.2 (M ⁺ +1).

Example 41 Synthesis of Compound 11210, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-isopropyl -N-phenylpiperidine-4-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpi prepared in step 3 of Example 39 Ferridine-4-carboxamide hydrochloride (0.050 g, 0.107 mmol), acetone (0.012 mL, 0.161 mmol) and sodium triacetoxyborohydride (0.034 g, 0.161 mmol) were diluted with dichloromethane ( 4 mL) was stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.020 g, 39.5 %) Was obtained in the form of a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.85 (t, 1H, J = 17.4 Hz), 7.75 (d, 1H, J = 9.5 Hz), 7.46 (d, 1H, J = 25.1 Hz), 7.38 (d , 3H, J = 2.9 Hz), 7.01 (d, 2H, J = 2.6 Hz), 6.97-6.81 (m, 1H), 5.08-4.98 (m, 2H), 3.59 (s, 1H), 3.38 (d, 1H, J = 17.5 Hz), 2.87 (d, 2H, J = 199.2 Hz), 2.30 (d, 3H, J = 82.5 Hz), 1.95 (d, 3H, J = 47.9 Hz), 1.40 (s, 6H) ; LRMS (ES) m / z 473.1 (M ⁺ +1).

Example 42: Synthesis of Compound 11211, 1-acetyl-N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl)- N-phenylpiperidine-4-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpi prepared in step 3 of Example 39 Acetyl in a solution of ferridine-4-carboxamide hydrochloride (0.050 g, 0.107 mmol) and N, N-diisopropylethylamine (0.037 mL, 0.214 mmol) in dichloromethane (4 mL) at room temperature Chloride (0.008 mL, 0.118 mmol) was added and stirred at the same temperature for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 59.3%). ) Was obtained in the form of a colorless oil.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.87 (d, 1H, J = 7.8 Hz), 7.72 (d, 1H, J = 9.5 Hz), 7.56 (t, 1H, J = 7.2 Hz), 7.39 (s , 3H), 7.06 (d, 2H, J = 6.1 Hz), 6.92 (t, 1H, J = 51.6 Hz), 5.03 (t, 2H, J = 11.0 Hz), 4.54 (d, 1H, J = 11.3 Hz ), 3.75 (t, 1H, J = 41.8 Hz), 2.83 (d, 1H, J = 11.1 Hz), 2.41 (ddd, 3H, J = 79.6, 32.3, 14.8 Hz), 1.85 (d, 2H, J = 10.1 Hz), 1.79 1.62 (m, 4H); LRMS (ES) m / z 473.4 (M ⁺ +1).

Example 43 Synthesis of Compound 11212, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenyl- 1-propionylpiperidine-4-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpi prepared in step 3 of Example 39 Pyridine-4-carboxamide hydrochloride (0.050 g, 0.107 mmol) and N, N-diisopropylethylamine (0.037 mL, 0.214 mmol) in solution dissolved in dichloromethane (4 mL) at room temperature Onyl chloride (0.010 mL, 0.118 mmol) was added and stirred at the same temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 57.6%). ) Was obtained in the form of a colorless oil.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.87 (d, 1H, J = 7.8 Hz), 7.72 (d, 1H, J = 9.5 Hz), 7.56 (t, 1H, J = 7.1 Hz), 7.39 (d , 3H, J = 5.5 Hz), 7.05 (t, 2H, J = 13.9 Hz), 6.92 (t, 1H, J = 51.7 Hz), 5.02 (d, 3H, J = 27.7 Hz), 4.55 (s, 1H ), 3.92 3.68 (m, 1H), 2.96 2.66 (m, 2H), 2.45 (t, 2H, J = 10.5 Hz), 1.78 (d, 4H, J = 56.0 Hz), 1.13 (t, 3H, J = 7.1 Hz); LRMS (ES) m / z 487.2 (M ⁺ +1).

Example 44 Synthesis of Compound 11213, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-isobeauty Reel-N-phenylpiperidine-4-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpi prepared in step 3 of Example 39 Ferridine-4-carboxamide hydrochloride (0.050 g, 0.107 mmol) and N, N-diisopropylethylamine (0.037 mL, 0.214 mmol) were dissolved in dichloromethane (4 mL) at room temperature. Butyryl chloride (0.012 mL, 0.118 mmol) was added and stirred at the same temperature for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 56.0%). ) Was obtained in the form of a colorless oil.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.90-7.82 (m, 1H), 7.72 (t, 1H, J = 10.3 Hz), 7.56 (d, 1H, J = 6.6 Hz), 7.39 (d, 3H, J = 4.7 Hz), 7.06 (d, 2H, J = 3.0 Hz), 6.99-6.82 (m, 1H), 5.01 (d, 3H, J = 32.5 Hz), 4.56 (s, 1H), 3.91 (s, 1H), 2.76 (dd, 3H, J = 23.9, 18.5 Hz), 2.46 (d, 2H, J = 6.7 Hz), 2.31 (s, 1H), 1.82 (s, 1H), 1.29-1.20 (m, 2H ), 1.13-1.09 (m, 4H); LRMS (ES) m / z 501.3 (M ⁺ +1).

Example 45 Synthesis of Compound 11214, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenyl- 1- (2,2,2-trifluoroacetyl) piperidine-4-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpi prepared in step 3 of Example 39 Tridine-4-carboxamide hydrochloride (0.050 g, 0.107 mmol) and N, N-diisopropylethylamine (0.037 mL, 0.214 mmol) were dissolved in dichloromethane (4 mL) at room temperature. Fluoroacetic anhydride (0.017 mL, 0.118 mmol) was added and stirred at the same temperature for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 53.2% ) Was obtained in the form of a colorless oil.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.88 (d, 1H, J = 8.0 Hz), 7.72 (t, 1H, J = 20.1 Hz), 7.55 (dd, 1H, J = 20.6, 13.1 Hz), 7.42 (dd, 3H, J = 16.5, 7.5 Hz), 7.07 (d, 2H, J = 7.6 Hz), 7.01-6.85 (m, 1H), 5.04 (q, 2H, J = 14.8 Hz), 4.43 (d, 1H, J = 13.5 Hz), 3.97 (t, 1H, J = 24.0 Hz), 2.96 (t, 1H, J = 12.7 Hz), 2.65 (t, 1H, J = 12.3 Hz), 2.54 (dt, 1H, J = 16.1, 7.8 Hz), 1.97-1.83 (m, 2H), 1.75 (d, 2H, J = 13.3 Hz); LRMS (ES) m / z 527.3 (M ⁺ +1).

Example 46 Synthesis of Compound 11215, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1- (methyl Sulfonyl) -N-phenylpiperidine-4-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpi prepared in step 3 of Example 39 Pyridine-4-carboxamide hydrochloride (0.050 g, 0.107 mmol) and N, N-diisopropylethylamine (0.037 mL, 0.214 mmol) were dissolved in a solution of dichloromethane (4 mL) at room temperature. Insulfonyl chloride (0.009 mL, 0.118 mmol) was added and stirred at the same temperature for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 5% to 70%) to give the title compound (0.030 g, 55.1%). ) Was obtained in the form of a white solid.

¹ H NMR (700 MHz, CDCl ₃ ) δ 7.88 (d, 1H, J = 7.2 Hz), 7.73 (d, 1H, J = 9.2 Hz), 7.56 (t, 1H, J = 6.1 Hz), 7.39 (s , 3H), 7.06 (s, 2H), 6.93 (td, 1H, J = 51.6, 2.2 Hz), 5.03 (d, 2H, J = 14.7 Hz), 3.75 (d, 2H, J = 9.6 Hz), 2.74 (d, 3H, J = 2.3 Hz), 2.55 (t, 2H, J = 11.7 Hz), 2.36 (dd, 1H, J = 10.0, 7.3 Hz), 1.95 (dd, 2H, J = 23.5, 11.5 Hz) , 1.75 (d, 2H, J = 13.3 Hz); LRMS (ES) m / z 509.3 (M ⁺ +1).

Example 47 Synthesis of Compound 11232, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -1-methyl- N-phenylazetidine-3-carboxamide

[Step 1] Synthesis of tert-butyl 3-((2-fluoro-4- (methoxycarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate

Tert-butyl 3- (phenylcarbamoyl) azetidine-1-carboxylate (2.000 g, 7.237 mmol) prepared in step 1 of Example 8 was dissolved in tetrahydrofuran (80 mL) and the temperature was maintained at 0 ° C. Sodium hydride (60.00%, 0.579 g, 14.475 mmol) was added slowly and stirred for 20 minutes, then methyl 4- (bromomethyl) -3-fluorobenzoate (2.146 g, 8.685 mmol) was added and 50 ° C After further stirring for 12 hours at room temperature to lower the temperature to room temperature, water (20 mL) was added to the reaction mixture at 0 ° C and the reaction was terminated by stirring for 5 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 5% to 50%) to give the title compound (2.800 g, 87.4%) in the form of a colorless oil.

[Step 2] Synthesis of tert-butyl 3-((2-fluoro-4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate

Tert-butyl 3-((2-fluoro-4- (methoxycarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate (2.500 g, 5.650 mmol) and hydrazine mono prepared in step 1 The mixture of hydrate (5.481 mL, 112.997 mmol) in ethanol (100 mL) at room temperature was heated to reflux for 12 hours and then lowered to room temperature, and the reaction mixture was poured into water to remove the solvent under reduced pressure, and then dichloromethane. Extracted with phosphorus. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (2.400 g, 96.0%, white solid).

[Step 3] tert-Butyl 3-((2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) (phenyl) carbamoyl) azetidine Synthesis of -1-carboxylate

Tert-Butyl 3-((2-fluoro-4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate (1.200 g, 2.712 mmol) and triethylamine prepared in step 2 Trifluoroacetic anhydride (0.415 mL, 2.983 mmol) was added to a solution of (0.454 mL, 3.254 mmol) in dichloromethane (50 mL) at room temperature and stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (1.400 g, 95.9%, colorless oil).

[Step 4] tert-Butyl 3-((2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) (phenyl) carbamoyl) Synthesis of Azetidine-1-carboxylate

Tert-butyl 3-((2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) (phenyl) carbamoyl) ase prepared in step 3 Tidine-1-carboxylate (1.400 g, 2.600 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.929 g, 3.900 mmol) were tetrahydrofuran (100 mL) at room temperature. The mixture was heated to reflux for 12 hours and then lowered to room temperature, and the reaction mixture was removed from the solvent under reduced pressure, and then the concentrate was purified by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 10% to 30%). %) To give the title compound (0.800 g, 59.1%) as a white solid.

[Step 5] N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylazetidine-3-car Synthesis of Voxamide Hydrochloride

Tert-Butyl 3-((2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) (phenyl) carbamoyl prepared in step 4 Hydrochloric acid (4.00 M solution in dioxane, 1.921 mL, 7.685 mmol) was added to a solution of azetidine-1-carboxylate (0.800 g, 1.537 mmol) in dichloromethane (50 mL) at room temperature and at the same temperature. Stir for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was suspended by pouring diethyl ether (50 mL) into the concentrate, filtered and the solid obtained was washed with diethyl ether and dried to give the title compound (0.600 g, 85.4%). Obtained in white solid form.

[Step 6] Synthesis of Compound 11232

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylazetidine-3- prepared in step 5 Sodium triacetoxyborohydride in a solution of carboxamide hydrochloride (0.050 g, 0.109 mmol) and formaldehyde (37.00% solution in water, 0.012 mL, 0.164 mmol) in dichloromethane (10 mL) at room temperature (0.035 g, 0.164 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 20%) to give the title compound (0.017 g, 35.8%) as a yellow solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.92-7.84 (m, 1H), 7.73 (t, 1H, J = 15.4 Hz), 7.60-7.51 (m, 1H), 7.37 (d, 3H, J = 14.7 Hz), 6.93 (dd, 2H, J = 32.2, 3.1 Hz), 5.11-5.00 (m, 2H), 3.84-3.58 (m, 4H), 3.49-3.40 (m, 1H), 2.66-2.51 (m, 3H); LRMS (ES) m / z 435.2 (M ⁺ +1).

Example 48 Synthesis of Compound 11233, 1-ethyl-N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl)- N-phenylazetidine-3-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylase prepared in step 5 of Example 47 Sodium triacetoxyborohydride (0.035 g, 0.164) in a solution of thidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and acetaldehyde (0.009 mL, 0.164 mmol) in room temperature (10 mL) mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.015 g, 30.6%) as a brown solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.88 (d, 1H, J = 7.7 Hz), 7.72 (t, 1H, J = 15.3 Hz), 7.58 (t, 1H, J = 6.9 Hz), 7.40 (d , 3H, J = 39.7 Hz, 6.96 (t, 2H, J = 20.0 Hz), 5.11 4.95 (m, 2H), 3.40 (d, 5H, J = 67.9 Hz), 2.62 (d, 2H, J = 4.5 Hz), 0.95 (d, 3H, J = 71.5 Hz); LRMS (ES) m / z 449.3 (M ⁺ +1).

Example 49 Synthesis of Compound 11234, 1-acetyl-N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl)- N-phenylazetidine-3-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylase prepared in step 5 of Example 47 Acetyl chloride in a solution of thidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) in dichloromethane (10 mL) at room temperature (0.009 mL, 0.120 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; dichloromethane / methanol = 0% to 20%) to give the title compound (0.027 g, 53.3%) as a yellow solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.94-7.83 (m, 1H), 7.75 (t, 1H, J = 9.4 Hz), 7.62-7.54 (m, 1H), 7.39 (s, 3H), 6.99 ( d, 2H, J = 5.4 Hz), 5.08 (s, 2H), 4.47 (t, 1H, J = 7.0 Hz), 4.08-4.01 (m, 1H), 3.94 (t, 1H, J = 8.4 Hz), 3.70 (t, 1H, J = 9.5 Hz), 3.38-3.27 (m, 1H), 1.84 (s, 3H); LRMS (ES) m / z 463.3 (M ⁺ +1).

Example 50 Synthesis of Compound 11235, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenyl- 1-propionylazetidine-3-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylase prepared in step 5 of Example 47 Propionyl chloride (0.011 mL) in a solution of thydine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) in room temperature (10 mL) 0.120 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.012 g, 23.0%) as a white solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.87 (dd, 1H, J = 23.0, 10.1 Hz), 7.75 (d, 1H, J = 9.5 Hz), 7.61 (dt, 1H, J = 15.0, 7.6 Hz) , 7.44-7.34 (m, 3H), 7.00 (d, 2H, J = 5.7 Hz), 5.13-5.02 (m, 2H), 4.41 (d, 1H, J = 76.8 Hz), 3.92 (dd, 2H, J = 97.6, 59.0 Hz), 3.69 (dd, 1H, J = 59.2, 21.2 Hz), 3.40-3.28 (m, 1H), 2.11 (d, 2H, J = 51.5 Hz), 1.13-1.05 (m, 3H) ; LRMS (ES) m / z 477.2 (M ⁺ +1).

Example 51 Synthesis of Compound 11236, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -1-isobeauty Reel-N-phenylazetidine-3-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylase prepared in step 5 of Example 47 Isobeauty in a solution of thidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) in dichloromethane (10 mL) at room temperature Reyl chloride (0.013 mL, 0.120 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.036 g, 67.1%) as a white solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.87 (t, 1H, J = 10.4 Hz), 7.74 (d, 1H, J = 9.6 Hz), 7.61 (dt, 1H, J = 29.5, 7.6 Hz), 7.45 -7.33 (m, 3H), 6.98 (dd, 2H, J = 28.1, 7.6 Hz), 5.15-4.97 (m, 2H), 4.38 (dd, 1H, J = 60.8, 56.4 Hz), 4.14-3.57 (m , 3H), 3.39-3.28 (m, 1H), 2.45-2.32 (m, 1H), 1.07 (s, 6H); LRMS (ES) m / z 491.3 (M ⁺ +1).

Example 52 Synthesis of Compound 11237, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -1- (methyl Sulfonyl) -N-phenylazetidine-3-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylase prepared in step 5 of Example 47 Methanesulfonate in a solution of thidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) in dichloromethane (10 mL) at room temperature Ponyl chloride (0.009 mL, 0.120 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.026 g, 47.7%) as a white solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.89 (t, 1H, J = 9.1 Hz), 7.75 (d, 1H, J = 9.4 Hz), 7.57 (t, 1H, J = 7.5 Hz), 7.40 (d , 3H, J = 1.5 Hz), 6.98 (d, 2H, J = 3.7 Hz), 5.08 (s, 2H), 4.13 (t, 2H, J = 7.5 Hz), 3.70 (t, 2H, J = 8.3 Hz ), 3.36 (p, 1H, J = 7.9 Hz), 2.91 (s, 3H); LRMS (ES) m / z 499.2 (M ⁺⁺ l).

Example 53 Synthesis of Compound 11238, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-methyl- N-phenylazetidine-3-carboxamide

[Step 1] tert-Butyl 3-((4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) (phenyl) carbamoyl) azetidine-1 Synthesis of Carboxylate

Tert-Butyl 3-((2-fluoro-4- (hydrazinecarbonyl) benzyl) (phenyl) carbamoyl) azetidine-1-carboxylate (1.200 g, 2.712 mmol) prepared in step 2 of Example 47 And triethylamine (0.454 mL, 3.254 mmol) in a solution of dichloromethane (50 mL) at room temperature were added difluoroacetic anhydride (0.371 mL, 2.983 mmol) and stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (1.400 g, 99.2%, colorless oil).

[Step 2] tert-Butyl 3-((4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) (phenyl) carbamoyl) Synthesis of Azetidine-1-carboxylate

Tert-butyl 3-((4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) (phenyl) carbamoyl) azetidine-prepared in step 1 1-carboxylate (1.400 g, 2.690 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.961 g, 4.035 mmol) were mixed in tetrahydrofuran (100 mL) at room temperature. The mixture was heated to reflux for 12 hours, then lowered to room temperature, the reaction mixture was removed from the solvent under reduced pressure, and the concentrate was then subjected to column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 10% to 30%). Purification and concentration to afford the title compound (0.700 g, 51.8%) as a white solid.

[Step 3] N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylazetidine-3-car Synthesis of Voxamide Hydrochloride

Tert-butyl 3-((4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) (phenyl) carbamoyl prepared in step 2 To a solution of azetidine-1-carboxylate (0.700 g, 1.393 mmol) in dichloromethane (50 mL) at room temperature, hydrochloric acid (4.00 M solution in dioxane, 1.741 mL, 6.965 mmol) was added at the same temperature. Stir for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was suspended by pouring diethyl ether (50 mL) into the concentrate, filtered and the solid obtained was washed with diethyl ether and dried to give the title compound (0.600 g, 98.1%). Obtained in white solid form.

[Step 4] Synthesis of Compound 11238

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylazetidine-3- prepared in step 3 Sodium triacetoxyborohydride in a solution of carboxamide hydrochloride (0.050 g, 0.114 mmol) and formaldehyde (37.00% solution in water, 0.013 mL, 0.171 mmol) in dichloromethane (10 mL) at room temperature (0.036 g, 0.171 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.010 g, 21.1%) as a white solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.88 (d, 1H, J = 7.8 Hz), 7.73 (d, 1H, J = 9.6 Hz), 7.61-7.53 (m, 1H), 7.35 (t, 3H, J = 9.7 Hz), 7.15 (d, 1H, J = 6.8 Hz), 6.97 (dd, 2H, J = 29.0, 22.5 Hz), 5.11-4.97 (m, 2H), 3.24 (dd, 4H, J = 67.4 , 30.6 Hz), 2.32 (s, 3H), 2.00 1.68 (m, 1H); LRMS (ES) m / z 417.3 (M ⁺ +1).

Example 54: Synthesis of Compound 11239, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-ethyl- N-phenylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylase prepared in step 3 of Example 53 In a solution of thidine-3-carboxamide hydrochloride (0.050 g, 0.114 mmol) and acetaldehyde (0.010 mL, 0.171 mmol) in dichloromethane (10 mL) at room temperature, sodium triacetoxyborohydride ( 0.036 g, 0.171 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.017 g, 34.7%) as a yellow solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.91-7.83 (m, 1H), 7.74 (d, 1H, J = 9.7 Hz), 7.57-7.49 (m, 1H), 7.44 7.34 (m, 3H), 7.02 -6.83 (m, 3H), 5.10-4.99 (m, 2H), 3.71-3.59 (m, 2H), 3.52 (dd, 2H, J = 19.3, 11.2 Hz), 3.49-3.37 (m, 1H), 2.84 2.72 (m, 2 H), 1.13-1.00 (m, 3 H); LRMS (ES) m / z 431.3 (M ⁺ +1).

Example 55 Synthesis of Compound 11240, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-isopropyl -N-phenylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylase prepared in step 3 of Example 53 Sodium triacetoxyborohydride (0.036) in a solution of tidine-3-carboxamide hydrochloride (0.050 g, 0.114 mmol) and acetone (0.013 mL, 0.171 mmol) in dichloromethane (10 mL) at room temperature g, 0.171 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.025 g, 49.4%) as a yellow solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.92-7.82 (m, 1H), 7.73 (t, 1H, J = 8.8 Hz), 7.54 (t, 1H, J = 7.5 Hz), 7.38 (d, 3H, J = 5.3 Hz), 7.04-6.82 (m, 3H), 5.03 (d, 2H, J = 21.2 Hz), 3.63-3.34 (m, 5H), 2.80-2.67 (m, 1H), 1.03 (t, 6H , J = 7.8 Hz); LRMS (ES) m / z 445.3 (M ⁺ +1).

Example 56 Synthesis of Compound 11241, 1-acetyl-N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl)- N-phenylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylase prepared in step 3 of Example 53 Acetyl chloride in a solution of thydine-3-carboxamide hydrochloride (0.050 g, 0.114 mmol) and N, N-diisopropylethylamine (0.039 mL, 0.228 mmol) in dichloromethane (10 mL) at room temperature (0.009 mL, 0.125 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.014 g, 27.6%) as a yellow solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.88 (d, 1H, J = 7.9 Hz), 7.73 (t, 1H, J = 12.4 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.39 (d , 3H, J = 5.2 Hz), 7.01-6.82 (m, 3H), 5.10-5.05 (m, 2H), 4.48 (t, 1H, J = 7.1 Hz), 4.09-4.01 (m, 1H), 3.94 ( t, 1H, J = 8.3 Hz), 3.70 (t, 1H, J = 9.3 Hz), 3.36-3.27 (m, 1H), 1.50 1.43 (m, 3H); LRMS (ES) m / z 445.3 (M ⁺ +1).

Example 57 Synthesis of Compound 11242, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenyl- 1-propionylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylase prepared in step 3 of Example 53 Propionyl in a solution of thydine-3-carboxamide hydrochloride (0.050 g, 0.114 mmol) and N, N-diisopropylethylamine (0.039 mL, 0.228 mmol) in dichloromethane (10 mL) at room temperature Chloride (0.011 mL, 0.125 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.017 g, 32.5%) as a yellow solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.88 (d, 1H, J = 7.9 Hz), 7.74 (d, 1H, J = 9.7 Hz), 7.57 (dd, 1H, J = 19.2, 11.7 Hz), 7.40 (dd, 3H, J = 16.9, 7.9 Hz), 7.03-6.83 (m, 3H), 5.08 (s, 2H), 4.56-4.32 (m, 1H), 4.03 (ddd, 4H, J = 153.6, 33.8, 26.6 Hz), 3.36-3.28 (m, 1H), 2.89-2.80 (m, 1H), 2.07 (d, 2H, J = 8.1 Hz), 1.10 (t, 3H, J = 7.6 Hz); LRMS (ES) m / z 459.3 (M ⁺ +1).

Example 58: Synthesis of Compound 11243, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-isobeauty Reel-N-phenylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylase prepared in step 3 of Example 53 Isobeauty in a solution of thidine-3-carboxamide hydrochloride (0.050 g, 0.114 mmol) and N, N-diisopropylethylamine (0.039 mL, 0.228 mmol) in dichloromethane (10 mL) at room temperature Reyl chloride (0.013 mL, 0.125 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.023 g, 42.7%) as a white solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.88 (dd, 1H, J = 8.0, 1.2 Hz), 7.74 (dd, 1H, J = 9.7, 1.1 Hz), 7.61-7.54 (m, 1H), 7.39 ( dt, 3H, J = 11.8, 4.2 Hz), 7.02-6.83 (m, 3H), 5.14-4.97 (m, 2H), 4.50 (s, 1H), 4.00 (d, 2H, J = 56.0 Hz), 3.74 -3.61 (m, 1H), 3.38-3.24 (m, 1H), 2.43-2.34 (m, 1H), 1.07 (d, 6H, J = 25.4 Hz); LRMS (ES) m / z 473.3 (M ⁺ +1).

Example 59: Synthesis of Compound 11244, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenyl- 1- (2,2,2-trifluoroacetyl) azetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylase prepared in step 3 of Example 53 Tidine-3-carboxamide hydrochloride (0.050 g, 0.114 mmol) and N, N-diisopropylethylamine (0.039 mL, 0.228 mmol) were dissolved in dichloromethane (10 mL) at room temperature. 2,2-trifluoroacetic anhydride (0.018 mL, 0.125 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate, 20 × 20 × 1 mm; methanol / dichloromethane = 10%) to give the title compound (0.005 g, 8.8%) as a white solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.89 (d, 1H, J = 7.9 Hz), 7.76 (d, 1H, J = 9.6 Hz), 7.57 (dd, 1H, J = 15.6, 8.0 Hz), 7.42 (d, 3H, J = 3.2 Hz), 7.02 6.83 (m, 3H), 5.13-5.07 (m, 2H), 4.74-4.67 (m, 1H), 4.30-4.24 (m, 1H), 4.19 (t, 1H, J = 9.1 Hz), 3.87 (t, 1H, J = 9.8 Hz), 3.47 (dt, 1H, J = 22.3, 7.9 Hz); LRMS (ES) m / z 499.1 (M ⁺ +1).

Example 60 Synthesis of Compound 11245, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1- (methyl Sulfonyl) -N-phenylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylase prepared in step 3 of Example 53 Methanesulfonate in a solution of thidine-3-carboxamide hydrochloride (0.050 g, 0.114 mmol) and N, N-diisopropylethylamine (0.040 mL, 0.228 mmol) in dichloromethane (10 mL) at room temperature Ponyl chloride (0.010 mL, 0.125 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.013 g, 23.7%) as a white solid.

¹ H NMR (CDCl ₃ , 700 MHz) δ 7.88 (d, 1H, J = 7.9 Hz), 7.75 (d, 1H, J = 9.6 Hz), 7.55 (dd, 1H, J = 18.1, 10.7 Hz), 7.40 (d, 3H, J = 1.6 Hz), 7.02-6.84 (m, 3H), 5.07 (d, 2H, J = 14.4 Hz), 4.14 (t, 2H, J = 7.5 Hz), 3.71 (t, 2H, J = 8.3 Hz), 3.39 3.32 (m, 1 H), 2.91 (s, 3 H); LRMS (ES) m / z 481.2 (M ⁺ +1).

Example 61 Synthesis of Compound 11246, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylacet Amide

[Step 1] Synthesis of methyl 3-fluoro-4-((N-phenylacetamido) methyl) benzoate

Methyl 3-fluoro-4-((phenylamino) methyl) benzoate (0.150 g, 0.579 mmol) and N, N-diisopropylethylamine (0.199 mL, 1.157 mmol) were diluted with dichloromethane (10 Acetyl chloride (0.045 mL, 0.636 mmol) was added to the solution dissolved in mL) and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.158 g, 90.6%) as a colorless oil.

[Step 2] Synthesis of N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N-phenylacetamide

Methyl 3-fluoro-4-((N-phenylacetamido) methyl) benzoate (0.158 g, 0.524 mmol) and nitrogen oxide (0.495 mL, 10.487 mmol) prepared in step 1 were added to ethanol (10 mL) at room temperature. ), The mixture was heated to reflux for 5 hours, and then cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.150 g, 94.9%, colorless oil).

[Step 3] Synthesis of N- (2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) -N-phenylacetamide

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N-phenylacetamide (0.075 g, 0.249 mmol) and triethylamine (0.069 mL, 0.498 mmol) prepared in step 2 were diluted at room temperature. Trifluoroacetic anhydride (0.042 mL, 0.299 mmol) was added to the solution dissolved in chloromethane (10 mL) and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.090 g, 91.0%, colorless oil).

[Step 4] Synthesis of Compound 11246

N- (2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) -N-phenylacetamide (0.090 g, 0.227 prepared in step 3) mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.081 g, 0.340 mmol) were mixed in dichloromethane (10 mL) and irradiated with microwave for 30 minutes at 150 ° C. After heating, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.004 g, 4.7%) as a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.84 (dd, 1H, J = 8.0, 1.6 Hz), 7.68 (dd, 1H J = 9.7, 1.4 Hz), 7.60 (t, J = 7.6 Hz, 1H), 7.36-7.28 (m, 3H), 7.05 (dd, 2H, J = 7.9, 1.4 Hz), 5.03 (s, 2H), 1.91 (s, 3H); LRMS (ES) m / z 380.2 (M ⁺ +1).

Example 62: Synthesis of Compound 11247, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylacet Amide

[Step 1] Synthesis of N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N-phenylacetamide

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N-phenylacetamide (0.075 g, 0.249 mmol) and triethylamine (0.069 mL, 0.498 mmol) prepared in step 2 of Example 61. To the solution dissolved in dichloromethane (10 mL) at room temperature was added 2,2-difluoroacetic anhydride (0.032 mL, 0.299 mmol) and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.093 g, 98.5%, colorless oil).

[Step 2] Synthesis of Compound 11247

N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N-phenylacetamide (0.093 g, 0.245 mmol) prepared in step 1 And 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.088 g, 0.368 mmol) were mixed in dichloromethane (10 mL) and irradiated with microwaves and heated at 150 ° C. for 30 minutes. Thereafter, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.005 g, 5.6%) as a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.69 (dd, J = 9.8, 1.5 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H) , 7.37-7.30 (m, 3H), 7.06-7.03 (m, 2H), 6.90 (t, J = 48.6 Hz, 1H), 5.04 (s, 2H), 1.93 (s, 3H); LRMS (ES) m / z 362.2 (M ⁺ +1).

Example 63 Synthesis of Compound 11325, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) -1-methylazetidine-3-carboxamide

[Step 1] Synthesis of tert-butyl 3-((2-fluoro-4- (methoxycarbonyl) benzyl) (3-fluorophenyl) carbamoyl) azetidine-1-carboxylate

tert-Butyl 3-((3-fluorophenyl) carbamoyl) azetidine-1-carboxylate (0.550 g, 1.869 mmol) was dissolved in tetrahydrofuran (80 mL) and sodium hydride while maintaining the temperature at 0 ° C. (60.00%, 0.149 g, 3.737 mmol) was added slowly and stirred for 20 minutes, then methyl 4- (bromomethyl) -3-fluorobenzoate (0.508 g, 2.056 mmol) was added and 12 h at 50 ° C. After further stirring to lower the temperature to room temperature, water (20 mL) was added to the reaction mixture at 0 ° C. and the reaction was terminated by stirring for 5 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 5% to 50%) to give the title compound (0.700 g, 81.4%) as a white solid.

[Step 2] Synthesis of tert-butyl 3-((2-fluoro-4- (hydrazinecarbonyl) benzyl) (3-fluorophenyl) carbamoyl) azetidine-1-carboxylate

Tert-butyl 3-((2-fluoro-4- (methoxycarbonyl) benzyl) (3-fluorophenyl) carbamoyl) azetidine-1-carboxylate (0.700 g, 1.520 mmol) prepared in step 1 ) And a mixture of hydrazine monohydrate (1.475 mL, 30.403 mmol) in ethanol (50 mL) at room temperature were heated to reflux for 12 hours, and then lowered to room temperature, and the reaction mixture was removed from the solvent under reduced pressure. Poured and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.600 g, 85.7%, white solid).

[Step 3] tert-Butyl 3-((4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) (3-fluorophenyl) carbamoyl) Synthesis of Azetidine-1-carboxylate

Tert-butyl 3-((2-fluoro-4- (hydrazinecarbonyl) benzyl) (3-fluorophenyl) carbamoyl) azetidine-1-carboxylate (0.600 g, 1.303 mmol) prepared in step 2 And difluoroacetic anhydride (0.178 mL, 1.433 mmol) were added to a solution of triethylamine (0.218 mL, 1.564 mmol) in dichloromethane (50 mL) at room temperature and stirred at the same temperature for 4 hours. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.600 g, 85.5%, colorless oil).

[Step 4] tert-Butyl 3-((4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) (3-fluorophenyl Synthesis of Carbamoyl) azetidine-1-carboxylate

Tert-butyl 3-((4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) (3-fluorophenyl) carbamoyl prepared in step 3 Azetidine-1-carboxylate (0.600 g, 1.114 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess reagent, 0.398 g, 1.671 mmol) were added to tetrahydrofuran (15 The mixture was added to the mL), and the mixture was irradiated with microwaves and heated at 150 ° C. for 30 minutes, and then the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 5% to 30%) to give the title compound (0.500 g, 86.2%) as a white solid.

[Step 5] N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3-fluorophenyl) Synthesis of Azetidine-3-Carboxamide Hydrochloride

Tert-butyl 3-((4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) (3-fluoro prepared in step 4) Hydrochloric acid (4.00 M solution in dioxane, 1.201 mL, 4.803 mmol) was added to a solution of phenyl) carbamoyl) azetidine-1-carboxylate (0.500 g, 0.961 mmol) in dichloromethane (50 mL) at room temperature. And stirred at the same temperature for 12 hours. After removing the solvent under reduced pressure, the reaction mixture was suspended by pouring diethyl ether (50 mL) into the concentrate, filtered and the resulting solid was washed with diethyl ether and dried to give the title compound (0.430 g, 98.0%). Obtained in white solid form.

[Step 6] Synthesis of Compound 11325

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3-fluorophenyl prepared in step 5 Sodium tridine in a solution of azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and formaldehyde (37.00% solution in water, 0.012 mL, 0.164 mmol) in dichloromethane (10 mL) at room temperature Acetoxyborohydride (0.035 g, 0.164 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to afford the title compound (0.007 g, 14.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.6 Hz), 7.74 (dd, 1H, J = 9.8, 1.5 Hz), 7.53 (t, 1H, J = 7.6 Hz) , 7.34 (td, 1H, J = 8.2, 6.4 Hz), 7.09 (td, 1H, J = 8.3, 2.3 Hz), 6.93 (dd, 1H, J = 68.9, 34.4 Hz), 6.76-6.66 (m, 2H ), 4.99 (d, 2H, J = 19.7 Hz), 3.60 (dd, 2H, J = 18.8, 10.8 Hz), 3.46 (t, 2H, J = 8.0 Hz), 3.35 (dt, 1H, J = 16.2, 8.1 Hz), 2.44 (d, 3H, J = 13.4 Hz); LRMS (ES) m / z 435.2 (M ⁺ +1).

Example 64 Synthesis of Compound 11326, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1-ethyl- N- (3-fluorophenyl) azetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 Sodium triacetate in a solution of aceticaldehyde (0.009 mL, 0.164 mmol) and acetaldehyde (0.009 mL, 0.164 mmol) in dichloromethane (10 mL) at room temperature. Toxyborohydride (0.035 g, 0.164 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.007 g, 14.3%) in the form of a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.5 Hz), 7.73 (dd, 1H, J = 9.8, 1.5 Hz), 7.54 (t, 1H, J = 7.6 Hz) , 7.33 (td, 1H, J = 8.1, 6.4 Hz), 7.08 (td, 1H, J = 8.3, 1.9 Hz), 6.93 (dd, 1H, J = 69.2, 34.1 Hz), 6.78-6.69 (m, 2H ), 4.99 (d, 2H, J = 19.8 Hz), 3.50-3.18 (m, 5H), 2.59 (q, 2H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.2 Hz); LRMS (ES) m / z 449.3 (M ⁺ +1).

Example 65 Synthesis of Compound 11327, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) -1-propylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 -Fluorophenyl) azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and propioaldehyde (0.010 g, 0.164 mmol) in solution dissolved in dichloromethane (10 mL) at room temperature Acetoxyborohydride (0.035 g, 0.164 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.017 g, 33.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (dd, 1H, J = 8.0, 1.5 Hz), 7.72 (dd, 1H, J = 9.8, 1.5 Hz), 7.51 (dd, 1H, J = 15.7, 8.0 Hz), 7.32 (tt, 1H, J = 11.9, 5.9 Hz), 7.07 (td, 1H, J = 8.1, 2.1 Hz), 6.90 (dd, 1H, J = 58.6, 44.7 Hz), 6.77-6.68 (m , 2H), 4.99 (d, 2H, J = 16.3 Hz), 3.61-3.47 (m, 2H), 3.47 3.31 (m, 3H), 2.57 (dd, 2H, J = 18.4, 10.5 Hz), 1.39 (dq , 2H, J = 14.9, 7.4 Hz), 0.90 0.81 (m, 3H); LRMS (ES) m / z 463.2 (M ⁺ +1).

Example 66 Synthesis of Compound 11328, 1-Butyl-N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl)- N- (3-fluorophenyl) azetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 -Fluorophenyl) azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and butyraldehyde (0.012 g, 0.164 mmol) in solution dissolved in dichloromethane (10 mL) at room temperature Acetoxyborohydride (0.035 g, 0.164 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to afford the title compound (0.020 g, 38.4%) in the form of a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (dd, 1H, J = 8.0, 1.5 Hz), 7.73 (dd, 1H, J = 9.8, 1.5 Hz), 7.51 (t, 1H, J = 7.6 Hz) , 7.34 (dt, 1H, J = 14.2, 6.5 Hz), 7.13-7.05 (m, 1H), 6.90 (dd, 1H, J = 58.6, 44.7 Hz), 6.77-6.64 (m, 2H), 4.99 (d , 2H, J = 13.6 Hz), 3.71-3.56 (m, 2H), 3.56-3.38 (m, 3H), 2.67 (dd, 2H, J = 19.4, 11.4 Hz), 1.42-1.21 (m, 4H), 0.92-0.79 (m, 3 H); LRMS (ES) m / z 477.3 (M ⁺ +1).

Example 67 Synthesis of Compound 11329, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) -1-isopropylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 -Fluorophenyl) azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and acetone (0.012 mL, 0.164 mmol) in sodium triacetox in a solution of dichloromethane (10 mL) at room temperature. Ciborohydride (0.035 g, 0.164 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 20%) to give the title compound (0.010 g, 19.8%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.5 Hz), 7.73 (dd, 1H, J = 9.8, 1.5 Hz), 7.54 (t, 1H, J = 7.5 Hz) , 7.33 (tt, 1H, J = 12.4, 6.2 Hz), 7.07 (td, 1H, J = 8.2, 2.0 Hz), 7.05-6.77 (m, 1H), 6.78-6.68 (m, 2H), 4.98 (d , 2H, J = 19.6 Hz), 3.43 (s, 2H), 3.37-3.22 (m, 3H), 2.61-2.48 (m, 1H), 1.02-0.92 (m, 6H); LRMS (ES) m / z 463.2 (M ⁺ +1).

Example 68 Synthesis of Compound 11330, 1-acetyl-N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl)- N- (3-fluorophenyl) azetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 -Fluorophenyl) azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) at room temperature in dichloromethane (10 mL) Acetyl chloride (0.009 mL, 0.120 mmol) was added to the dissolved solution, and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 90%) to give the title compound (0.016 g, 31.6%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.6 Hz), 7.74 (dd, 1H, J = 9.8, 1.6 Hz), 7.60-7.51 (m, 1H), 7.40- 7.30 (m, 1H), 7.09 (td, 1H, J = 8.2, 2.4 Hz), 7.06-6.78 (m, 1H), 6.74 (dt, 2H, J = 7.9, 6.8 Hz), 5.02 (d, 2H, J = 19.1 Hz), 4.45 (s, 1H), 3.99 (d, 2H, J = 33.8 Hz), 3.79-3.68 (m, 1H), 3.31 (tt, 1H, J = 8.8, 6.3 Hz), 1.82 ( s, 3H); LRMS (ES) m / z 463.2 (M ⁺ +1).

Example 69: Synthesis of Compound 11331, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) -1-propionylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 -Fluorophenyl) azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) at room temperature in dichloromethane (10 mL) Propionyl chloride (0.011 mL, 0.120 mmol) was added to the solution, and stirred for 18 hours at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 90%) to give the title compound (0.018 g, 34.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.5 Hz), 7.73 (dd, 1H, J = 9.8, 1.4 Hz), 7.54 (dd, 1H, J = 16.0, 8.3 Hz), 7.35 (dd, 1H, J = 14.4, 8.1 Hz), 7.13-7.05 (m, 1H), 7.05-6.77 (m, 1H), 6.74 (dd, 2H, J = 7.5, 5.3 Hz), 5.07 -4.99 (m, 2H), 4.35 (dd, 1H, J = 24.2, 19.7 Hz), 4.14-3.79 (m, 2H), 3.79-3.65 (m, 1H), 3.32 (tt, 1H, J = 8.9, 6.4 Hz), 2.11-1.94 (m, 2H), 1.08 (dd, 3H, J = 10.0, 5.1 Hz); LRMS (ES) m / z 477.3 (M ⁺ +1).

Example 70: Synthesis of Compound 11332, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) -1-isobutylylazetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 -Fluorophenyl) azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) at room temperature in dichloromethane (10 mL) Isobutyryl chloride (0.013 mL, 0.120 mmol) was added to the solution, which was stirred for 18 hours at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 90%) to give the title compound (0.021 g, 39.1%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.4 Hz), 7.72 (dt, 1H, J = 15.7, 7.8 Hz), 7.54 (dd, 1H, J = 15.6, 8.0 Hz), 7.36 (dd, 1H, J = 8.3, 6.3 Hz), 7.15-7.05 (m, 1H), 7.05-6.78 (m, 1H), 6.78-6.68 (m, 2H), 5.02 (d, 2H, J = 19.0 Hz), 4.47 (s, 1H), 4.07-3.62 (m, 3H), 3.38-3.25 (m, 1H), 2.48-2.30 (m, 1H), 1.11-0.95 (m, 6H); LRMS (ES) m / z 491.2 (M ⁺ +1).

Example 71: Synthesis of Compound 11333, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) -1- (methylsulfonyl) azetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 -Fluorophenyl) azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) at room temperature in dichloromethane (10 mL) To the solution dissolved in methanesulfonyl chloride (0.009 mL, 0.120 mmol) was added and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 90%) to give the title compound (0.012 g, 22.0%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.5 Hz), 7.74 (dd, 1H, J = 9.8, 1.4 Hz), 7.52 (dd, 1H, J = 15.1, 7.5 Hz), 7.36 (dd, 1H, J = 11.1, 5.0 Hz), 7.14-7.07 (m, 1H), 7.05-6.78 (m, 1H), 6.78-6.69 (m, 2H), 5.08-4.98 (m, 2H), 4.16-4.07 (m, 2H), 3.77-3.68 (m, 2H), 3.41-3.28 (m, 1H), 2.89 (d, 3H, J = 5.3 Hz); LRMS (ES) m / z 499.2 (M ⁺⁺ l).

Example 72: Synthesis of Compound 11334, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1- (ethyl Sulfonyl) -N- (3-fluorophenyl) azetidine-3-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 prepared in step 5 of Example 63 -Fluorophenyl) azetidine-3-carboxamide hydrochloride (0.050 g, 0.109 mmol) and N, N-diisopropylethylamine (0.038 mL, 0.219 mmol) at room temperature in dichloromethane (10 mL) Ethanesulfonyl chloride (0.015 g, 0.120 mmol) was added to the solution, which was stirred for 1 hour at the same temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 90%) to give the title compound (0.020 g, 35.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.6 Hz), 7.79-7.70 (m, 1H), 7.56 (dd, 1H, J = 15.7, 8.1 Hz), 7.35 ( td, 1H, J = 8.1, 6.4 Hz), 7.10 (td, 1H, J = 8.1, 2.1 Hz), 7.07-6.78 (m, 1H), 6.78-6.70 (m, 2H), 5.10-4.98 (m, 2H), 4.22-4.10 (m, 2H), 3.74-3.61 (m, 2H), 3.41-3.30 (m, 1H), 3.00-2.90 (m, 2H), 1.34 (q, 3H, J = 7.4 Hz) ; LRMS (ES) m / z 513.2 (M ⁺ +1).

Example 73: Synthesis of Compound 11339, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 Fluorophenyl) acetamide

[Step 1] Synthesis of methyl 4- (bromomethyl) -3-fluorobenzoate

Methyl 3-fluoro-4-methylbenzoate (8.500 g, 50.544 mmol), 1-bromopyrrolidin-2,5-one (NBS, 9.446 g, 53.071 mmol) and azobisisobutyronitrile (AIBN , 0.415 g, 2.527 mmol) was added to dichloromethane (150 mL) at room temperature, and the mixture was heated to reflux for 18 hours, lowered to room temperature, poured into the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (7.600 g, 60.9%) as a white solid.

[Step 2] Synthesis of methyl 3-fluoro-4-(((3-fluorophenyl) amino) methyl) benzoate

3-fluoroaniline (1.000 g, 8.999 mmol), methyl 4- (bromomethyl) -3-fluorobenzoate (2.446 g, 9.899 mmol) prepared in step 1 and N, N-diisopropylethylamine (3.102 mL, 17.999 mmol) in acetonitrile (50 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 24 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (2.170 g, 87.0%) as a colorless oil.

[Step 3] Synthesis of methyl 3-fluoro-4-((N- (3-fluorophenyl) acetamido) methyl) benzoate

Methyl 3-fluoro-4-(((3-fluorophenyl) amino) methyl) benzoate (0.200 g, 0.721 mmol) prepared in step 2 and N, N-diisopropylethylamine (0.251 mL, 1.443 mmol) was added to a solution of dichloromethane (10 mL) at room temperature, and acetyl chloride (0.061 mL, 0.866 mmol) was added thereto and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.210 g, 91.2%) in the form of a yellow oil.

[Step 4] Synthesis of N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) acetamide

Methyl 3-fluoro-4-((N- (3-fluorophenyl) acetamido) methyl) benzoate (0.210 g, 0.658 mmol) and hydrazine hydrate (0.658 g, 13.153 mmol) prepared in step 3 were prepared. The mixture mixed with ethanol (10 mL) at room temperature was heated to reflux for 18 hours and then lowered to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.187 g, 89.0%, white foamy solid).

[Step 5] Synthesis of Compound 11339

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) acetamide (0.090 g, 0.282 mmol) and triethylamine (0.079 mL, 0.564) prepared in step 4 mmol) was added to 2,2-difluoroacetic anhydride (0.037 mL, 0.338 mmol) in a solution dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.071 g, 66.4%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (dt, 1H, J = 13.6, 6.8 Hz), 7.75-7.66 (m, 1H), 7.63-7.52 (m, 1H), 7.32 (tt, 1H, J = 12.0, 6.0 Hz), 7.10-7.01 (m, 1H), 6.94-6.75 (m, 3H), 5.02 (s, 2H), 1.95 (s, 3H); LRMS (ES) m / z 380.2 (M ⁺ +1).

Example 74: Synthesis of Compound 11340, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N- (3 Fluorophenyl) acetamide

[Step 1] N- (2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) -N- (3-fluorophenyl) acetamide Synthesis of

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) acetamide (0.090 g, 0.282 mmol) and triethylamine (prepared in step 4 of Example 73) 0.079 mL, 0.564 mmol) was added trifluoroacetic anhydride (0.048 mL, 0.338 mmol) to a solution of dichloromethane (10 mL) at room temperature and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.112 g, 95.7%, yellow oil).

[Step 2] Synthesis of Compound 11340

N- (2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) benzyl) -N- (3-fluorophenyl) acetate prepared in step 1 Amide (0.120 g, 0.289 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.103 g, 0.433 mmol) were mixed in tetrahydrofuran (10 mL) and irradiated with microwaves to room temperature. After heating for 1 hour at, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.029 g, 25.3%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.4 Hz), 7.73 (d, 1H, J = 9.7 Hz), 7.61 (t, 1H, J = 7.6 Hz), 7.34 (td, 1H, J = 8.1, 6.5 Hz), 7.05 (td, 1H, J = 8.3, 2.1 Hz), 6.84 (dd, 2H, J = 22.0, 8.5 Hz), 5.03 (s, 2H), 1.95 ( s, 3H); LRMS (ES) m / z 398.1 (M ⁺ +1).

Example 75 Synthesis of Compound 11341, N-((5- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) -N- Phenylisonicotinamide

[Step 1] Synthesis of Methyl 6-((N-phenylisonicotinamido) methyl) nicotinate

Isonicotinyl chloride in a solution of methyl 6-((phenylamino) methyl) nicotinate (0.050 g, 0.206 mmol) and triethylamine (0.058 mL, 0.413 mmol) in dichloromethane (10 mL) at room temperature. Hydrochloride (0.044 g, 0.248 mmol) was added and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.071 g, 99.0%) as a colorless oil.

[Step 2] Synthesis of N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) -N-phenylisonicotinamide

Methyl 6-((N-phenylisonicotinamido) methyl) nicotinate (0.071 g, 0.204 mmol) and hydrazine hydrate (0.199 mL, 4.088 mmol) prepared in step 1 were added to ethanol (10 mL) at 90 ° C. The dissolved solution was stirred at the same temperature for 1 hour, and then the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.070 g, 98.6%, colorless oil).

[Step 3] Synthesis of Compound 11341

N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) -N-phenylisonicotinamide (0.070 g, 0.202 mmol) and triethylamine (0.056 mL, 0.403 mmol) prepared in step 2 were prepared. To a solution dissolved in dichloromethane (10 mL) at room temperature, 2,2-difluoroacetic anhydride (0.028 mL, 0.262 mmol) was added and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.045 g, 54.8%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, 1H, J = 1.7 Hz), 8.47 (d, 2H, J = 5.3 Hz), 8.38 (dd, 1H, J = 8.2, 2.2 Hz), 7.63 (d, 1H, J = 8.2 Hz), 7.25-7.16 (m, 5H), 7.16-7.09 (m, 2H), 7.09-6.79 (m, 1H), 5.28 (d, 2H, J = 21.7 Hz); LRMS (ES) m / z 408.3 (M ⁺ +1).

Example 76 Synthesis of Compound 11356, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) propioamide

[Step 1] Synthesis of methyl 3-fluoro-4-((N- (3-fluorophenyl) propioamido) methyl) benzoate

Methyl 3-fluoro-4-(((3-fluorophenyl) amino) methyl) benzoate (0.100 g, 0.361 mmol) prepared in step 2 of Example 73 and N, N-diisopropylethylamine ( 0.125 mL, 0.721 mmol) was added propionyl chloride (0.041 mL, 0.469 mmol) to a solution of dichloromethane (10 mL) at room temperature and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.100 g, 83.2%) in the form of a colorless oil.

[Step 2] Synthesis of N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) propioamide

Methyl 3-fluoro-4-((N- (3-fluorophenyl) propioamido) methyl) benzoate (0.100 g, 0.300 mmol) and hydrazine monohydrate (0.292 mL, 6.000 mmol) prepared in step 1 ) In a mixture of ethanol (6 mL) at room temperature was heated to reflux for 18 hours and then lowered to room temperature, the reaction mixture was removed under reduced pressure, and the title compound was used without further purification (0.098 g, 98.0%, Colorless oil).

[Step 3] of N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N- (3-fluorophenyl) propioamide synthesis

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) propioamide (0.098 g, 0.294 mmol) prepared in step 2 and triethylamine (0.082 mL, 0.588 mmol) was added 2,2-difluoroacetic anhydride (0.038 mL, 0.353 mmol) to a solution dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.120 g, 99.2%, colorless oil).

[Step 4] Synthesis of Compound 11356

N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N- (3-fluorophenyl) propioamide prepared in step 3 (0.120 g, 0.292 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methaneimite (Burgess reagent, 0.104 g, 0.438 mmol) were mixed in tetrahydrofuran (10 mL) and irradiated with microwave at 150 ° C. After heating for 1 hour at, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.018 g, 15.7%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.29 (d, 1H, J = 1.7 Hz), 8.47 (d, 2H, J = 5.3 Hz), 8.38 (dd, 1H, J = 8.2, 2.2 Hz), 7.63 (d, 1H, J = 8.2 Hz), 7.25-7.16 (m, 5H), 7.16-7.09 (m, 2H), 7.09-6.79 (m, 1H), 5.28 (d, 2H, J = 21.7 Hz); LRMS (ES) m / z 408.3 (M ⁺ +1).

Example 77 Synthesis of Compound 11357, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) butyamide

[Step 1] Synthesis of methyl 3-fluoro-4-((N- (3-fluorophenyl) butyramido) methyl) benzoate

Methyl 3-fluoro-4-(((3-fluorophenyl) amino) methyl) benzoate (0.100 g, 0.361 mmol) prepared in step 2 of Example 73 and N, N-diisopropylethylamine ( Butyryl chloride (0.049 mL, 0.469 mmol) was added to a solution of 0.126 mL, 0.721 mmol) in dichloromethane (10 mL) at room temperature, and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO 2, 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.103 g, 82.2%) as a colorless oil.

[Step 2] Synthesis of N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) butyramide

Methyl 3-fluoro-4-((N- (3-fluorophenyl) butyramido) methyl) benzoate (0.103 g, 0.297 mmol) and hydrazine monohydrate (0.288 mL, 5.930 mmol) prepared in step 1 ) In a mixture of ethanol (6 mL) at room temperature was heated to reflux for 18 hours and then lowered to room temperature, the reaction mixture was removed under reduced pressure, and the title compound was used without further purification (0.100 g, 97.1%, Colorless oil).

[Step 3] of N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N- (3-fluorophenyl) butyramide synthesis

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) butyramide (0.100 g, 0.288 mmol) prepared in step 2 and triethylamine (0.080 mL, 0.576 mmol) was added 2,2-difluoroacetic anhydride (0.038 mL, 0.345 mmol) to a solution dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.120 g, 98.0%, colorless oil).

[Step 4] Synthesis of Compound 11357

N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N- (3-fluorophenyl) butyramide prepared in step 3 (0.120 g, 0.282 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methaneimdate (Burgess reagent, 0.101 g, 0.423 mmol) were mixed with tetrahydrofuran (10 mL) and irradiated with microwave at 150 ° C. After heating for 1 hour at, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.012 g, 10.4%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.1, 1.7 Hz), 7.72 (dd, 1H, J = 9.8, 1.7 Hz), 7.59 (t, 1H, J = 7.6 Hz) , 7.33 (td, 1H, J = 8.1, 6.3 Hz), 7.11-7.01 (m, 1H), 6.93-6.75 (m, 3H), 5.02 (s, 2H), 2.10 (t, 2H, J = 7.4 Hz ), 1.64 (h, 2H, J = 7.4 Hz), 0.86 (t, 3H, J = 7.4 Hz); LRMS (ES) m / z 408.2 (M ⁺ +1).

Example 78: Synthesis of Compound 11358, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N- (3 -Fluorophenyl) -3-methylbutaneamide

[Step 1] Synthesis of methyl 3-fluoro-4-((N- (3-fluorophenyl) -3-methylbutamido) methyl) benzoate

Methyl 3-fluoro-4-(((3-fluorophenyl) amino) methyl) benzoate (0.100 g, 0.361 mmol) prepared in step 2 of Example 73 and N, N-diisopropylethylamine ( 0.125 mL, 0.721 mmol) was added 3-methylbutanyl chloride (0.057 mL, 0.469 mmol) in a solution of dichloromethane (10 mL) at room temperature and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.115 g, 88.2%) in the form of a colorless oil.

[Step 2] Synthesis of N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) -3-methylbutaneamide

Methyl 3-fluoro-4-((N- (3-fluorophenyl) -3-methylbutamido) methyl) benzoate (0.115 g, 0.318 mmol) and hydrazine monohydrate (0.309 mL) prepared in step 1 , 6.364 mmol) in ethanol (6 mL) at room temperature was heated to reflux for 18 hours, then lowered to room temperature, the reaction mixture was removed under reduced pressure, and the title compound was used without further purification (0.105 g, 91.3%, colorless oil).

[Step 3] N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N- (3-fluorophenyl) -3-methyl Synthesis of Butaneamide

N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) -N- (3-fluorophenyl) -3-methylbutaneamide (0.105 g, 0.291 mmol) and triethylamine (prepared in step 2) 0.081 mL, 0.581 mmol) was added 2,2-difluoroacetic anhydride (0.038 mL, 0.349 mmol) to a solution of dichloromethane (10 mL) at room temperature and stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.122 g, 95.6%, colorless oil).

[Step 4] Synthesis of Compound 11358

N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) -N- (3-fluorophenyl) -3- prepared in step 3 Methyl butaneamide (0.140 g, 0.319 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.114 g, 0.478 mmol) were mixed in tetrahydrofuran (10 mL) and irradiated with microwaves. After heating at 150 ° C. for 1 hour, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.011 g, 8.2%) as a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, 1H, J = 8.0, 1.7 Hz), 7.72 (dd, 1H, J = 9.8, 1.7 Hz), 7.60 (t, 1H, J = 7.6 Hz) , 7.33 (td, 1H, J = 8.1, 6.3 Hz), 7.10-7.02 (m, 1H), 6.93-6.74 (m, 3H), 5.03 (s, 2H), 2.18 (dq, 1H, J = 13.5, 6.7 Hz), 2.01 (d, 2H, J = 7.0 Hz), 0.87 (d, 6H, J = 6.6 Hz); LRMS (ES) m / z 422.3 (M ⁺ +1).

Example 79 Synthesis of Compound 11359, N- (3-fluorophenyl) -N-((5- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) pyridine -2-yl) methyl) isonicotinamide

[Step 1] Synthesis of Methyl 6-((N- (3-fluorophenyl) isonicotinamido) methyl) nicotinate

Methyl 6-(((3-fluorophenyl) amino) methyl) nicotinate (0.200 g, 0.768 mmol) and N, N-diisopropylethylamine (0.268 mL, 1.537 mmol) were dichloromethane at room temperature. Isonicotin oil chloride hydrochloride (0.178 g, 0.999 mmol) was added to the solution dissolved in (10 mL) and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.277 g, 98.7%) in the form of a colorless oil.

[Step 2] Synthesis of N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) isonicotinamide

Methyl 6-((N- (3-fluorophenyl) isonicotinamido) methyl) nicotinate (0.277 g, 0.758 mmol) and hydrazine monohydrate (0.737 mL, 15.163 mmol) prepared in step 1 were diluted with ethanol ( 10 mL), irradiated with microwaves and heated at 120 ° C for 1 hour, the reaction was terminated by lowering the temperature to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.220 g, 79.4%, white foamy solid).

[Step 3] N- (3-fluorophenyl) -N-((5- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) pyridin-2-yl) methyl) Synthesis of Isonicotinamide

N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) isonicotinamide (0.100 g, 0.274 mmol) and triethylamine (0.076) prepared in step 2 mL, 0.547 mmol) was added trifluoroacetic anhydride (0.050 mL, 0.356 mmol) to a solution dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature for 1 hour. After the reaction mixture was freed of the solvent under reduced pressure, the title compound was used without further purification (0.121 g, 95.8%, colorless oil).

[Step 4] Synthesis of Compound 11359

N- (3-fluorophenyl) -N-((5- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) pyridin-2-yl) methyl prepared in step 3 Isonicotinamide (0.130 g, 0.282 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.101 g, 0.423 mmol) are mixed with tetrahydrofuran (10 mL) and microwave After irradiation and heating at 150 ° C. for 30 minutes, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.024 g, 19.2%) in the form of a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.37-9.26 (m, 1H), 8.61-8.48 (m, 2H), 8.40 (dd, 1H, J = 8.2, 2.2 Hz), 7.63 (d, 1H, J = 8.2 Hz), 7.32-7.27 (m, 2H), 7.18 (td, 1H, J = 8.2, 6.2 Hz), 7.02 (dt, 1H, J = 9.4, 2.3 Hz), 6.96-6.87 (m, 2H) , 5.28 (s, 2 H); LRMS (ES) m / z 444.3 (M ⁺ +1).

Example 80 Synthesis of Compound 11360, N-((5- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) -N- (3-fluorophenyl) isonicotinamide

[Step 1] N-((5- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) pyridin-2-yl) methyl) -N- (3-fluorophenyl) isonicotin Synthesis of Amide

Tri with N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) isonicotinamide (0.120 g, 0.328 mmol) prepared in step 2 of Example 79 To a solution of ethylamine (0.092 mL, 0.657 mmol) in dichloromethane (10 mL) at room temperature was added 2,2-difluoroacetic anhydride (0.046 mL, 0.427 mmol) and stirred at the same temperature for 1 hour. . After removing the solvent under reduced pressure the reaction mixture was used without further purification (0.140 g, 96.1%, colorless oil).

[Step 2] Synthesis of Compound 11360

N-((5- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) pyridin-2-yl) methyl) -N- (3-fluorophenyl) isoprepared in step 1 Nicotinamide (0.140 g, 0.316 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.113 g, 0.474 mmol) were mixed in tetrahydrofuran (10 mL) and irradiated with microwaves. After heating at 150 ° C. for 1 hour, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (0.021 g, 15.6%) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35-9.24 (m, 1H), 8.57-8.48 (m, 2H), 8.40 (dd, 1H, J = 8.2, 2.2 Hz), 7.62 (d, 1H, J = 8.2 Hz), 7.24 (d, 2H, J = 1.5 Hz), 7.18 (td, 1H, J = 8.2, 6.3 Hz), 7.08-6.98 (m, 1H), 6.95-6.80 (m, 3H), 5.27 (s, 2H); LRMS (ES) m / z 426.3 (M ⁺ +1).

Example 81 Synthesis of Compound 11376, N-((5- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) -N- (3-fluorophenyl) nicotinamide

[Step 1] Synthesis of Methyl 6-(((3-fluorophenyl) amino) methyl) nicotinate

Sodium triacetoxyborohydride in a solution of 3-fluoroaniline (1.500 g, 13.499 mmol) and methyl 6-formylnicotinate (2.452 g, 14.849 mmol) in dichloromethane (10 mL) at room temperature (4.291 g, 20.248 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (2.830 g, 80.5%) as a yellow solid.

[Step 2] Synthesis of methyl 6-((N- (3-fluorophenyl) nicotinamido) methyl) nicotinate

Methyl 6-(((3-fluorophenyl) amino) methyl) nicotinate (0.100 g, 0.384 mmol) and triethylamine (0.107 mL, 0.768 mmol) prepared in step 1 were diluted with dichloromethane ( 10 mL) was added nicotin oil chloride hydrochloride (0.103 g, 0.576 mmol) and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.111 g, 79.1%) in the form of a yellow oil.

[Step 3] Synthesis of N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) nicotinamide

Methyl 6-((N- (3-fluorophenyl) nicotinamido) methyl) nicotinate (0.111 g, 0.304 mmol) and hydrazine monohydrate (0.295 mL, 6.076 mmol) prepared in step 2 were ethanol at room temperature. The mixture in (10 mL) was heated to reflux for 18 hours, then lowered to room temperature, the reaction mixture was removed from the solvent under reduced pressure, and the title compound was used without further purification (0.108 g, 97.3%, yellow oil).

[Step 4] N-((5- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) pyridin-2-yl) methyl) -N- (3-fluorophenyl) nicotinamide Synthesis of

N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) nicotinamide (0.111 g, 0.304 mmol) and triethylamine (0.085 mL) prepared in step 3 , 0.608 mmol) was added 2,2-difluoroacetic anhydride (0.050 mL, 0.456 mmol) to a solution of tetrahydrofuran (10 mL) at room temperature, and stirred at 80 ° C. for 18 hours, and then the temperature was maintained at room temperature. Lowered to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.133 g, 98.7%, colorless oil).

[Step 5] Synthesis of Compound 11376

N-((5- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) pyridin-2-yl) methyl) -N- (3-fluorophenyl) nicotine prepared in step 4 Amide (0.140 g, 0.316 mmol) and 1-methoxy-N-triethylammoniosulfonyl-methaneimdate (Burgess reagent, 0.226 g, 0.947 mmol) were mixed in tetrahydrofuran (10 mL) and irradiated with microwave to 150. After heating at 1 ° C. for 1 hour, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.018 g, 13.4%) as a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.35-9.24 (m, 2H), 8.81 (d, 1H, J = 5.1 Hz), 8.64-8.51 (m, 2H), 8.41 (ddd, 1H, J = 8.3 , 3.6, 2.3 Hz), 7.81-7.62 (m, 2H), 7.26-7.15 (m, 2H), 6.88-6.42 (m, 2H), 5.32 (d, 2H, J = 2.8 Hz); LRMS (ES) m / z 426.4 (M ⁺ +1).

Example 82: Synthesis of Compound 11414, N-((5- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) -1- Methyl-N-phenylpiperidine-4-carboxamide

[Step 1] Synthesis of methyl 6-((1- (tert-butoxycarbonyl) -N-phenylpiperidine-4-carboxamido) methyl) nicotinate

Sodium hydride (60.00%, 0.079) was dissolved in tert-butyl 4- (phenylcarbamoyl) piperidine-1-carboxylate (0.400 g, 1.314 mmol) in tetrahydrofuran (30 mL) and the temperature maintained at 0 ° C. g, 1.971 mmol) was added slowly and stirred for 20 minutes. Methyl 6- (bromomethyl) nicotinate (0.333 g, 1.446 mmol) was added and further stirred at room temperature for 12 hours, and then water (2 mL) was added to the reaction mixture at 0 ° C. and stirred for 5 minutes. Terminated. Water was added to the reaction mixture, followed by extraction with dichloromethane, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, followed by concentration under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 5% to 40%) to afford the title compound (0.390 g, 65.4%) in the form of a solid foam.

[Step 2] Synthesis of methyl 6-((N-phenylpiperidine-4-carboxamido) methyl) nicotinate hydrochloride

Methyl 6-((1- (tert-butoxycarbonyl) -N-phenylpiperidine-4-carboxamido) methyl) nicotinate (0.390 g, 0.860 mmol) prepared in step 1 was diluted with Methane (30 mL) was added, and hydrochloric acid (4.00 M solution in dioxane, 2.150 mL, 8.599 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 12 hours. After removing the solvent under reduced pressure the reaction mixture was used without further purification (0.330 g, 98.4%, white solid).

[Step 3] Synthesis of methyl 6-((1-methyl-N-phenylpiperidine-4-carboxamido) methyl) nicotinate

Methyl 6-((N-phenylpiperidine-4-carboxamido) methyl) nicotinate hydrochloride (0.150 g, 0.385 mmol) prepared in step 2, formaldehyde (37.00% solution in water, 0.143 mL, 1.924 mmol) and sodium triacetoxyborohydride (0.204 g, 0.962 mmol) in dichloromethane (20 mL) at room temperature were stirred at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, followed by concentration under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.120 g, 84.9%) in the form of a solid foam.

[Step 4] Synthesis of N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) -1-methyl-N-phenylpiperidine-4-carboxamide

Methyl 6-((1-methyl-N-phenylpiperidine-4-carboxamido) methyl) nicotinate (0.120 g, 0.327 mmol) and hydrazine monohydrate (0.079 mL, 1.633 mmol) prepared in step 3 ) Was dissolved in ethanol (10 mL) at room temperature and heated to reflux for 12 hours, the temperature was lowered to room temperature to terminate the reaction. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO 2, 4 g cartridge; methanol / dichloromethane = 5% to 30%) to give the title compound (0.115 g, 95.8% ) Is obtained in the form of a solid foam.

[Step 5] Synthesis of Compound 11414

N -((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) -1-methyl-N-phenylpiperidine-4-carboxamide (0.200 g, 0.544 mmol) prepared in step 4, 2 A solution of, 2-difluoroacetic anhydride (0.178 mL, 1.633 mmol) and triethylamine (0.152 mL, 1.089 mmol) in tetrahydrofuran (10 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by chromatography (SiO ₂ plate, 20 × 20 × 1 mm; methanol / dichloromethane = 20%) to give the title compound (0.002 g, 0.9%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.30-9.24 (m, 1H), 8.36 (dd, 1H, J = 8.2, 2.2 Hz), 7.58-7.33 (m, 5H), 7.25-7.22 (m, 1H ), 7.10-6.80 (m, 1H), 5.05 (s, 2H), 3.46 (d, 2H, J = 11.1 Hz), 3.26 (d, 2H, J = 11.8 Hz), 2.91 (s, 2H), 2.74 (d, 3H, J = 4.1 Hz), 2.36 (s, 1H), 1.96 (d, 2H, J = 14.7 Hz); LRMS (ES) m / z 428.5 (M ⁺ +1).

Example 83: Synthesis of Compound 11418, N-((5- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) -N- (3-fluorophenyl) -1-methylpiperidine-4-carboxamide

[Step 1] Synthesis of methyl 6-((1- (tert-butoxycarbonyl) -N- (3-fluorophenyl) piperidine-4-carboxamido) methyl) nicotinate

tert-Butyl 4-((3-fluorophenyl) carbamoyl) piperidine-1-carboxylate (0.400 g, 1.241 mmol) was dissolved in tetrahydrofuran (30 mL) and sodium hydride was maintained at 0 ° C. Ride (60.00%, 0.074 g, 1.861 mmol) was added slowly and stirred for 20 minutes, after which methyl 6- (bromomethyl) nicotinate (0.314 g, 1.365 mmol) was added and further stirred at room temperature for 12 hours. Then, water (2 mL) was added to the reaction mixture at 0 ° C. and stirred for 5 minutes to terminate the reaction. Water was added to the reaction mixture, followed by extraction with dichloromethane, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, followed by concentration under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 5% to 40%) to give the title compound (0.400 g, 68.4%) as a foam solid.

[Step 2] Synthesis of methyl 6-((N- (3-fluorophenyl) piperidine-4-carboxamido) methyl) nicotinate hydrochloride

Methyl 6-((1- (tert-butoxycarbonyl) -N- (3-fluorophenyl) piperidine-4-carboxamido) methyl) nicotinate prepared in step 1 (0.400 g, 0.848 mmol) was dissolved in dichloromethane (30 mL) and hydrochloric acid (4.00 M solution in dioxane, 2.121 mL, 8.483 mmol) was added at 0 ° C. and stirred at room temperature for 12 hours. After the reaction mixture was freed from the solvent under reduced pressure, the title compound was used without further purification (0.340 g, 98.3%, white solid).

[Step 3] Synthesis of methyl 6-((N- (3-fluorophenyl) -1-methylpiperidine-4-carboxamido) methyl) nicotinate

Methyl 6-((N- (3-fluorophenyl) piperidine-4-carboxamido) methyl) nicotinate hydrochloride (0.150 g, 0.368 mmol) prepared in step 2, formaldehyde (37.00% solution in water, 0.137 mL, 1.839 mmol) and sodium triacetoxyborohydride (0.156 g, 0.736 mmol) in dichloromethane (20 mL) at room temperature were stirred at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, followed by concentration under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.130 g, 91.7%) in the form of a solid foam.

[Step 4] Synthesis of N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) -1-methylpiperidine-4-carboxamide

Methyl 6-((N- (3-fluorophenyl) -1-methylpiperidine-4-carboxamido) methyl) nicotinate (0.130 g, 0.337 mmol) and hydrazine monohydrate prepared in step 3 The solution of (0.082 mL, 1.686 mmol) dissolved in ethanol (10 mL) at room temperature was heated to reflux for 12 hours, and then the temperature was lowered to room temperature to terminate the reaction. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 5% to 30%) to give the title compound (0.120 g, 92.3 %) Was obtained in the form of a solid foam.

[Step 5] Synthesis of Compound 11418

N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) -1-methylpiperidine-4-carboxamide (0.200 g) prepared in step 4 , 0.519 mmol) and triethylamine (0.145 mL, 1.038 mmol) in tetrahydrofuran (13 mL) and heated at room temperature for 2 hours by adding 2,2-difluoroacetic anhydride (0.085 mL, 0.778 mmol) After reflux, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, followed by extraction with dichloromethane, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, followed by concentration under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 15%), and then the obtained product was chromatographed again (SiO ₂ plate, 20 × 20). x 1 mm; methanol / dichloromethane = 10%) to give the title compound (0.015 g, 6.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25 (m, 1H), 8.38 (m, 1H), 7.54 (m, 1H), 7.35 (m, 1H), 7.10-6.82 (m, 4H), 5.05 ( s, 2H), 2.95 (m, 2H), 2.42-2.32 (m, 5H), 1.99-1.78 (m, 5H); LRMS (ES) m / z 446.4 (M ⁺ +1).

Example 84: Synthesis of Compound 11419, N-((5- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl) -1- Ethyl-N- (3-fluorophenyl) piperidine-4-carboxamide

[Step 1] Synthesis of methyl 6-((1-ethyl-N- (3-fluorophenyl) piperidine-4-carboxamido) methyl) nicotinate

Methyl 6-((N- (3-fluorophenyl) piperidine-4-carboxamido) methyl) nicotinate hydrochloride (0.150 g, 0.368 mmol) prepared in step 2 of Example 83, acet A solution of aldehyde (0.104 mL, 1.839 mmol) and sodium triacetoxyborohydride (0.156 g, 0.736 mmol) in dichloromethane (20 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, followed by concentration under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 10%) to give the title compound (0.130 g, 88.5%) in the form of a solid foam.

[Step 2] Synthesis of 1-ethyl-N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) piperidine-4-carboxamide

Methyl 6-((1-ethyl-N- (3-fluorophenyl) piperidine-4-carboxamido) methyl) nicotinate (0.130 g, 0.325 mmol) and hydrazine monohydrate prepared in step 1 The solution of (0.079 mL, 1.627 mmol) dissolved in ethanol (10 mL) at room temperature was heated to reflux for 12 hours, and then the temperature was lowered to room temperature to terminate the reaction. After the reaction mixture was freed from the solvent under reduced pressure, the concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 5% to 30%) to give the title compound (0.120 g, 92.3 %) Was obtained in the form of a solid foam.

[Step 3] Synthesis of Compound 11419

1-ethyl-N- (3-fluorophenyl) -N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) piperidine-4-carboxamide (0.200 g) prepared in step 2 , 0.501 mmol) and triethylamine (0.140 mL, 1.001 mmol) in tetrahydrofuran (13 mL) and heated at room temperature for 2 hours by adding 2,2-difluoroacetic anhydride (0.082 mL, 0.751 mmol) After reflux, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, followed by extraction with dichloromethane, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, followed by concentration under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 15%), and then the obtained product was chromatographed again (SiO ₂ plate, 20 × 20). x 1 mm; methanol / dichloromethane = 10%) to give the title compound (0.015 g, 6.5%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.25 (m, 1H), 8.37 (m, 1H), 7.52 (m, 1H), 7.36 (m, 1H), 7.12-6.82 (m, 4H), 5.04 ( s, 2H), 3.11 (m, 2H), 2.63-2.16 (m, 4H), 2.01-1.90 (m, 5H), 1.18 (m, 3H); LRMS (ES) m / z 460.5 (M ⁺ +1).

Example 85 Synthesis of Compound 11534, N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazole-2- Yl) -2-fluorobenzyl) -2- (pyrrolidin-1-yl) acetamide

[Step 1] Synthesis of 2- (benzyloxy) -N- (4-chloro-3-fluorophenyl) acetamide

4-chloro-3-fluoroaniline (1.000 g, 6.870 mmol), 2- (benzyloxy) acetic acid (1.179 mL, 8.244 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide ( EDC, 2.133 g, 13.740 mmol), 1H-benzo [d] [1,2,3] triazole-1-ol (HOBt, 1.857 g, 13.740 mmol) and N, N-diisopropylethylamine (2.393 mL , 13.740 mmol) was dissolved in dichloromethane (50 mL) at room temperature and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (1.880 g, 93.2%) as a yellow solid.

[Step 2] Synthesis of methyl 4-((2- (benzyloxy) -N- (3-chloro-4-fluorophenyl) acetamido) methyl) -3-fluorobenzoate

2- (benzyloxy) -N- (4-chloro-3-fluorophenyl) acetamide (1.880 g, 6.401 mmol) and potassium carbonate (1.327 g, 9.601 mmol) prepared in step 1 were tetrahydrogenated at 0 ° C. To a solution dissolved in furan (50 mL), methyl 4- (bromomethyl) -3-fluorobenzoate (1.898 g, 7.681 mmol) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (1.780 g, 60.5%) in the form of a yellow oil.

[Step 3] 2- (benzyloxy) - N - (4- (hydrazine-carbonyl) 2-fluorobenzyl) -acetamide Synthesis of (3-chloro-4-fluoro phenyl) - N

Methyl 4 prepared in Step 2 - ((2- (benzyloxy) - - N (3- chloro-4-fluorophenyl) acetamido) methyl) -3-fluoro-benzoate (1.780 g, 3.871 mmol) And a solution of hydrazine monohydrate (5.644 mL, 116.120 mmol) in ethanol (8 mL) / water (2 mL) at room temperature was stirred at 80 ° C. for 12 hours, and the reaction was terminated by lowering the temperature to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (1.580 g, 88.8%, yellow solid).

[Step 4] 2- (benzyloxy) -N- (3-chloro-4-fluorophenyl) -N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) Synthesis of 2-fluorobenzyl) acetamide

Prepared in step 3, 2- (benzyloxy) - N - (3-chloro-4-fluorophenyl) - N - (2-fluoro-4- (hydrazine-carbonyl) benzyl) -acetamide (1.580 g, 3.436 mmol) and triethylamine (0.958 mL, 6.871 mmol) were dissolved in dichloromethane (50 mL) at room temperature, and 2,2-difluoroacetic anhydride (0.513 mL, 4.123 mmol) was added thereto at the same temperature. Stir for hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (1.120 g, 60.6%) in the form of a colorless oil.

[Step 5] N- (3-chloro-4-fluorophenyl) -N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) Synthesis of 2-hydroxyacetamide

2- (benzyloxy) -N- (3-chloro-4-fluorophenyl) -N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl prepared in step 4 ) -2-fluorobenzyl) acetamide (0.880 g, 1.636 mmol) was dissolved in methanol (50 mL) at room temperature and slowly added 10% -Pd / C (600 mg) and attached hydrogen balloon at the same temperature for 5 hours. Was stirred. The reaction mixture was filtered through a pad of celite, water was poured into the filtrate from which the solid was removed, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.658 g, 89.8%) in the form of a yellow oil.

[Step 6] 2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluoro Synthesis of benzyl) amino) -2-oxoethyl methanesulfonate

N- (3-chloro-4-fluorophenyl) -N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl prepared in step 5 Methanesulfonyl in a solution of) -hydroxyacetamide (0.658 g, 1.470 mmol) and N, N-diisopropylethylamine (0.768 mL, 4.409 mmol) in dichloromethane (50 mL) at room temperature. Chloride (0.284 mL, 3.674 mmol) was added and stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 50%) to give the title compound (0.254 g, 34.0%) in the form of a yellow oil.

[Step 7] Synthesis of Compound 11534

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluoro prepared in step 6 Lobenzyl) amino) -2-oxoethyl methanesulfonate (0.050 g, 0.098 mmol), pyrrolidine (0.011 g, 0.148 mmol) and N, N-diisopropylethylamine (0.034 mL, 0.197 mmol) The solution dissolved in acetonitrile (5 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.013 g, 27.3%) in the form of a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91 (dd, 1H, J = 8.0, 1.7 Hz), 7.76 (dd, 1H, J = 9.9, 1.7 Hz), 7.65 (t, 1H, J = 7.6 Hz) , 7.29 (dd, 1H, J = 6.2, 2.6 Hz), 7.22-7.07 (m, 2H), 7.06-6.75 (m, 1H), 5.01 (s, 2H), 3.88-3.73 (m, 4H), 3.20 (t, 2H, J = 8.7 Hz), 2.17 (d, 4H, J = 6.2 Hz); LRMS (ES) m / z 483.4 (M ⁺ +1).

Example 86 Synthesis of Compound 11535, N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2- 1) -2-fluorobenzyl) -2-morpholinoacetamide

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) prepared in step 6 of Example 85 -2-fluorobenzyl) amino) -2-oxoethyl methanesulfonate (0.050 g, 0.098 mmol), morpholine (0.013 mL, 0.148 mmol) and N, N-diisopropylethylamine (0.034 mL, 0.197 mmol) was dissolved in acetonitrile (5 mL) at room temperature and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.042 g, 85.5%) as a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (ddd, 1H, J = 8.0, 4.9, 1.7 Hz), 7.73 (ddd, 1H, J = 9.8, 8.0, 1.7 Hz), 7.62 (td, 1H, J = 7.6, 2.3 Hz), 7.27-7.23 (m, 1H), 7.18-7.05 (m, 2H), 7.05-6.76 (m, 1H), 5.03-4.90 (m, 2H), 3.82 (dt, 4H, J = 23.4, 4.8 Hz), 3.27-3.04 (m, 2H), 2.77 (d, 4H, J = 55.3 Hz); LRMS (ES) m / z 499.5 (M ⁺ +1).

Example 87: Synthesis of Compound 11536, (S) -N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadia Zol-2-yl) -2-fluorobenzyl) -2- (3-hydroxypyrrolidin-1-yl) acetamide

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) prepared in step 6 of Example 85 -2-fluorobenzyl) amino) -2-oxoethyl methanesulfonate (0.050 g, 0.098 mmol), (S) -pyrrolidin-3-ol (0.013 g, 0.148 mmol) and N, N-dia A solution of isopropylethylamine (0.034 mL, 0.197 mmol) in acetonitrile (5 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 30%) to give the title compound (0.044 g, 89.6%) in the form of a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (t, 1H, J = 7.0 Hz), 7.79-7.51 (m, 2H), 7.24-7.05 (m, 3H), 6.92 (t, 1H, J = 51.8 Hz), 5.02 (s, 2H), 4.21-3.43 (m, 4H), 3.27 (d, 1H, J = 47.5 Hz), 2.49 (s, 5H); LRMS (ES) m / z 499.5 (M ⁺ +1).

Example 88: Synthesis of Compound 11537, (R) -N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadia Zol-2-yl) -2-fluorobenzyl) -2- (2- (hydroxymethyl) pyrrolidin-1-yl) acetamide

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) prepared in step 6 of Example 85 -2-fluorobenzyl) amino) -2-oxoethyl methanesulfonate (0.050 g, 0.098 mmol), (R) -pyrrolidin-2-ylmethanol (0.015 g, 0.148 mmol) and N, N- A solution of diisopropylethylamine (0.034 mL, 0.197 mmol) in acetonitrile (5 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 4 g cartridge; methanol / hexane = 0% to 15%) to give the title compound (0.019 g, 37.6%) in the form of a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (ddd, 1H, J = 8.2, 6.9, 1.7 Hz), 7.75 (ddd, 1H, J = 9.9, 6.1, 1.7 Hz), 7.60 (dt, 1H, J = 14.8, 7.6 Hz), 7.25-7.05 (m, 3H), 7.03-6.77 (m, 1H), 5.08-4.92 (m, 2H), 3.92-2.66 (m, 7H), 2.29-1.47 (m, 4H ); LRMS (ES) m / z 513.5 (M ⁺ +1).

Example 89: Synthesis of Compound 11538, (S) -1- (2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxa Diazol-2-yl) -2-fluorobenzyl) amino) -2-oxoethyl) pyrrolidine-2-carboxamide

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) prepared in step 6 of Example 85 -2-fluorobenzyl) amino) -2-oxoethyl methanesulfonate (0.050 g, 0.098 mmol), (S) -pyrrolidine-2-carboxamide (0.017 g, 0.148 mmol) and N, N Diisopropylethylamine (0.034 mL, 0.197 mmol) in acetonitrile (5 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 4 g cartridge; methanol / dichloromethane = 0% to 15%) to afford the title compound (0.041 g, 79.2%) in the form of a colorless oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (td, 1H, J = 7.4, 1.6 Hz), 7.75 (ddd, 1H, J = 9.8, 6.0, 1.6 Hz), 7.60 (dt, 1H, J = 14.8 , 7.5 Hz), 7.25-7.05 (m, 2H), 7.06-6.76 (m, 2H), 5.09-4.91 (m, 2H), 3.85-2.98 (m, 6H), 3.18-3.02 (m, 1H), 2.22-1.68 (m, 4H); LRMS (ES) m / z 526.5 (M ⁺ +1).

Example 90 Synthesis of Compound 11584, N-phenyl-N-((5- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) pyridin-2-yl) methyl Isonicotinamide

[Step 1] Synthesis of N-phenyl-N-((5- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) pyridin-2-yl) methyl) isonicotinamide

N-((5- (hydrazinecarbonyl) pyridin-2-yl) methyl) -N-phenylisonicotinamide (1.000 g, 2.879 mmol) and triethylamine (0.802 mL, prepared in step 2 of Example 75 5.757 mmol) was dissolved in tetrahydrofuran (30 mL), trifluoroacetic anhydride (0.813 mL, 5.757 mmol) was added thereto at room temperature, and the mixture was heated to reflux for 12 hours, and then the temperature was lowered to room temperature to terminate the reaction. Saturated aqueous ammonium chloride solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The title compound was used without further purification (0.750 g, 61.2%, colorless oil).

[Step 2] Synthesis of Compound 11584

N-phenyl-N-((5- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) pyridin-2-yl) methyl) isonicotinamide (0.900) prepared in step 1 g, 2.030 mmol) and a mixture of 1-methoxy-N-triethylammoniosulfonyl-methanimide (Burgess reagent, 0.484 g, 2.030 mmol) in tetrahydrofuran (15 mL) at room temperature were irradiated with microwaves. After heating at 150 ° C. for 30 minutes, the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, followed by extraction with dichloromethane, followed by filtration through a plastic filter to remove the solid residue and the aqueous layer, followed by concentration under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO ₂ , 80 g cartridge; ethyl acetate / hexane = 10% to 60%), and then the obtained product was chromatographed again (SiO ₂ , 40 g cartridge; ethyl Purification and concentration with acetate / hexane = 10% to 60%) afforded the title compound (0.470 g, 54.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.32 (m, 1H), 8.54 (m, 2H), 8.40 (m, 1H), 7.65 (m, 1H), 7.40 (m, 2H), 7.25 (m, 3H), 7.17 (m, 2H), 5.32 (s, 2H); LRMS (ES) m / z 426.4 (M ⁺ +1).

Example 91: Synthesis of Compound 11602, N- (3-chloro-4-fluorophenyl) -N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxa Diazol-2-yl) benzyl) tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[Step 1] Synthesis of N- (3-chloro-4-fluorophenyl) tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

3-chloro-4-fluoroaniline (0.700 g, 4.809 mmol), tetrahydro-2H-thiopyran-4-carboxylic acid 1,1-dioxide (0.943 g, 5.290 mmol), 1-ethyl-3- (3 -Dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl, 1.844 g, 9.618 mmol), 1H-benzo [d] [1,2,3] triazol-1-ol (HOBt, 1.300 g, 9.618 mmol ) And N, N-diisopropylethylamine (1.675 mL, 9.618 mmol) in dichloromethane (100 mL) at room temperature were stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 40 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.988 g, 67.2%) as a white solid.

[Step 2] Methyl 4-((N- (3-chloro-4-fluorophenyl) -1,1-dioxydotetrahydro-2H-thiopyran-4-carboxamido) methyl) -3- Synthesis of Fluorobenzoate

N- (3-chloro-4-fluorophenyl) tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (1.000 g, 3.271 mmol) and sodium hydride (60.00) prepared in step 1 %, 0.262 g, 6.541 mmol) was dissolved in N, N-dimethylformamide (50 mL) at room temperature in methyl 4- (bromomethyl) -3-fluorobenzoate (1.212 g, 4.906 mmol). It was added and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 100%) to give the title compound (1.240 g, 80.3%) as a white solid.

[Step 3] N- (3-Chloro-4-fluorophenyl) -N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) tetrahydro-2H-thiopyran-4-carboxamide 1 Synthesis of, 1-dioxide

Methyl 4-((N- (3-chloro-4-fluorophenyl) -1,1-dioxydotetrahydro-2H-thiopyran-4-carboxamido) methyl) -3 prepared in step 2) -A solution of fluorobenzoate (1.240 g, 2.628 mmol) and hydrazine monohydrate (2.554 mL, 52.554 mmol) in ethanol (20 mL) / water (5 mL) at room temperature was stirred at 80 ° C. for 5 hours. The reaction was terminated by lowering the temperature to room temperature. After removal of the solvent under reduced pressure the reaction mixture was used without further purification (1.180 g, 95.2%, yellow solid).

[Step 4] N- (3-chloro-4-fluorophenyl) -N- (2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl) Benzyl) tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

N- (3-chloro-4-fluorophenyl) -N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) tetrahydro-2H-thiopyran-4-carboxamide prepared in step 3 Trifluoroacetic anhydride (0.180 mL, 1.271 mmol) was dissolved in a solution of 1,1-dioxide (0.200 g, 0.424 mmol) and triethylamine (0.118 mL, 0.848 mmol) in tetrahydrofuran (10 mL) at room temperature. After addition and stirring at 80 ° C. for 1 hour, the temperature was lowered to room temperature to terminate the reaction. The reaction mixture was filtered on to remove the solid, and the filtrate was freed from solvent under reduced pressure, and then the concentrate was purified and concentrated by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%). The title compound (0.160 g, 66.5%) was obtained in the form of a colorless oil.

[Step 5] Synthesis of Compound 11602

N- (3-chloro-4-fluorophenyl) -N- (2-fluoro-4- (2- (2,2,2-trifluoroacetyl) hydrazine-1-carbonyl prepared in step 4 Benzyl) tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (0.160 g, 0.282 mmol) and triethylamine (0.079 mL, 0.563 mmol) at room temperature in dichloromethane (15 mL) Methanesulfonyl chloride (0.033 mL, 0.423 mmol) was added to the solution, which was then stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.030 g, 19.4%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (dd, 1H, J = 8.0, 1.7 Hz), 7.76 (dd, 1H, J = 9.8, 1.7 Hz), 7.54 (t, 1H, J = 7.6 Hz) , 7.21-7.12 (m, 2H), 6.91 (ddd, 1H, J = 8.7, 4.1, 2.7 Hz), 4.98 (s, 2H), 3.38-3.25 (m, 1H), 2.79 (ddd, 2H, J = 13.9, 9.9, 3.7 Hz), 2.50 (tt, 1H, J = 7.8, 3.6 Hz), 2.43-2.29 (m, 2H), 2.18-2.06 (m, 3H); LRMS (ES) 550.4 m / z (M ⁺ +1).

Example 92 Synthesis of Compound 11603, N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazole-2- I) -2-fluorobenzyl) tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

[Step 1] N- (3-chloro-4-fluorophenyl) -N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl) Synthesis of Tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide

N- (3-chloro-4-fluorophenyl) -N- (2-fluoro-4- (hydrazinecarbonyl) benzyl) tetrahydro-2H-thiopyran-4 prepared in step 3 of Example 91 2,2-difluoroacetic anhydride in a solution of carboxamide 1,1-dioxide (0.200 g, 0.424 mmol) and triethylamine (0.118 mL, 0.848 mmol) in tetrahydrofuran (10 mL) at room temperature. (0.158 mL, 1.271 mmol) was added and stirred at 80 ° C. for 2 hours, then the temperature was lowered to room temperature to terminate the reaction. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.170 g, 72.9%) as a colorless oil.

[Step 2] Synthesis of Compound 11603

N- (3-chloro-4-fluorophenyl) -N- (4- (2- (2,2-difluoroacetyl) hydrazine-1-carbonyl) -2-fluorobenzyl prepared in step 1 Tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (0.170 g, 0.309 mmol) and triethylamine (0.086 mL, 0.618 mmol) were added to dichloromethane (15 mL) at room temperature. Methanesulfonyl chloride (0.036 mL, 0.464 mmol) was added to the dissolved solution, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 80%) to give the title compound (0.015 g, 9.1%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (dd, 1H, J = 8.0, 1.7 Hz), 7.75 (dd, 1H, J = 9.9, 1.7 Hz), 7.52 (t, 1H, J = 7.6 Hz) , 7.21-7.10 (m, 2H), 7.06-6.76 (m, 2H), 4.97 (s, 2H), 3.37-3.26 (m, 2H), 2.79 (ddd, 2H, J = 13.9, 9.8, 3.6 Hz) , 2.50 (tt, 1H, J = 7.9, 3.6 Hz), 2.42-2.28 (m, 2H), 2.19-2.05 (m, 2H); LRMS (ES) m / z 532.3 (M ⁺ +1).

Example 93: Synthesis of Compound 11610, N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2- Yl) -2-fluorobenzyl) -2- (1,1-dioxydothiomorpholino) acetamide

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) prepared in step 6 of Example 85 2-fluorobenzyl) amino) -2-oxoethyl methanesulfonate (0.050 g, 0.098 mmol), thiomorpholine 1,1-dioxide (0.020 g, 0.148 mmol) and N, N-diisopropylethyl A solution of amine (0.034 mL, 0.197 mmol) in acetonitrile (5 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.030 g, 55.7%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (td, 1H, J = 7.7, 1.7 Hz), 7.74 (td, 1H, J = 9.8, 1.7 Hz), 7.56 (t, 1H, J = 7.5 Hz) , 7.19 (dd, 1H, J = 6.4, 2.6 Hz), 7.15 (t, 1H, J = 8.5 Hz), 7.09-6.99 (m, 1H), 6.97-6.77 (m, 1H), 4.99 (d, 2H , J = 5.7 Hz), 3.15-3.06 (m, 10H); LRMS (ES) m / z 547.4 (M ⁺ +1).

Example 94: Synthesis of Compound 11611, 2- (4-acetylpiperazin-1-yl) -N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl ) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) acetamide

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) prepared in step 6 of Example 85 -2-fluorobenzyl) amino) -2-oxoethyl methanesulfonate (0.050 g, 0.098 mmol), 1- (piperazin-1-yl) ethan-1-one (0.019 g, 0.148 mmol) and N A solution of, N-diisopropylethylamine (0.034 mL, 0.197 mmol) in acetonitrile (5 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.046 g, 86.5%) in the form of a brown oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (ddd, 1H, J = 8.0, 6.3, 1.7 Hz), 7.72 (td, 1H, J = 9.7, 1.7 Hz), 7.63-7.54 (m, 1H), 7.22 (dd, 1H, J = 6.4, 2.6 Hz), 7.12 (t, 1H, J = 8.5 Hz), 7.07-7.00 (m, 1H), 6.99-6.75 (m, 1H), 4.98 (d, 2H, J = 4.5 Hz), 3.62 (dt, 2H, J = 10.1, 4.9 Hz), 3.48 (dt, 2H, J = 9.9, 4.9 Hz), 3.00 (d, 2H, J = 8.3 Hz), 2.64-2.38 ( m, 4H), 2.04 (d, 3H, J = 1.1 Hz); LRMS (ES) m / z 540.4 (M ⁺ +1).

Example 95 Synthesis of Compound 11612, N- (3-Chloro-4-fluorophenyl) -2- (4- (cyclopropanecarbonyl) piperazin-1-yl) -N- (4- (5 -(Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) acetamide

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) prepared in step 6 of Example 85 -2-fluorobenzyl) amino) -2-oxoethyl methanesulfonate (0.050 g, 0.098 mmol), cyclopropyl (piperazin-1-yl) methanone (0.021 mL, 0.148 mmol) and N, N- A solution of diisopropylethylamine (0.034 mL, 0.197 mmol) in acetonitrile (5 mL) at room temperature was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 15%) to give the title compound (0.045 g, 80.8%) in the form of a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (td, 1H, J = 7.1, 6.2, 1.7 Hz), 7.73 (t, 1H, J = 9.6 Hz), 7.60 (t, 1H, J = 7.6 Hz) , 7.25-7.20 (m, 1H), 7.12 (t, 1H, J = 8.5 Hz), 7.04 (d, 1H, J = 6.4 Hz), 7.01-6.74 (m, 1H), 4.99 (d, 2H, J = 4.6 Hz), 3.68 (s, 4H), 3.03 (d, 2H, J = 12.1 Hz), 2.54 (d, 4H, J = 35.4 Hz), 1.68 (tt, 1H, J = 8.1, 4.6 Hz), 0.95 (dt, 2H, J = 6.5, 3.4 Hz), 0.74 (dq, 2H, J = 7.2, 3.8 Hz); LRMS (ES) m / z 566.4 (M ⁺ +1).

Example 96: Synthesis of Compound 11613, N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2- Yl) -2-fluorobenzyl) -2- (4- (methylsulfonyl) piperazin-1-yl) acetamide

[Step 1] N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2- Synthesis of Fluorobenzyl) -2- (piperazin-1-yl) acetamide

2-((3-chloro-4-fluorophenyl) (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) prepared in step 6 of Example 85 -2-fluorobenzyl) amino) -2-oxoethyl methanesulfonate (0.200 g, 0.394 mmol), piperazine (0.051 g, 0.591 mmol) and N, N-diisopropylethylamine (0.137 mL, 0.788 mmol) was dissolved in acetonitrile (10 mL) at room temperature and stirred for 18 hours at the same temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; ethyl acetate / hexane = 0% to 15%) to give the title compound (0.158 g, 80.6%) as a white solid.

[Step 2] Synthesis of Compound 11613

N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2 prepared in step 1 -Fluorobenzyl) -2- (piperazin-1-yl) acetamide (0.050 g, 0.100 mmol), methanesulfonyl chloride (0.012 mL, 0.151 mmol) and N, N-diisopropylethylamine (0.035 mL , 0.201 mmol) in room temperature (5 mL) was stirred at the same temperature for 18 hours. 1.0N hydrochloric acid solution was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.054 g, 93.4%) in the form of a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (ddd, 1H, J = 8.2, 6.4, 1.7 Hz), 7.71 (td, 1H, J = 9.8, 1.7 Hz), 7.57 (td, 1H, J = 7.7 , 7.2, 1.7 Hz), 7.20 (dd, 1H, J = 6.4, 2.6 Hz), 7.12 (t, 1H, J = 8.5 Hz), 7.03 (td, 1H, J = 5.3, 4.7, 1.7 Hz), 6.84 (dd, 1H, J = 51.7, 1.4 Hz), 4.98 (d, 2H, J = 4.6 Hz), 3.28-3.19 (m, 4H), 2.98 (s, 2H), 2.75 (d, 3H, J = 1.4 Hz), 2.59 (q, 4H, J = 5.7, 4.9 Hz); LRMS (ES) m / z 576.4 (M ⁺ +1).

Example 97: Synthesis of Compound 11614, N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2- Yl) -2-fluorobenzyl) -2- (4- (oxetan-3-yl) piperazin-1-yl) acetamide

N- (3-chloro-4-fluorophenyl) -N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2- prepared in Step 1 of Example 96 Yl) -2-fluorobenzyl) -2- (piperazin-1-yl) acetamide (0.050 g, 0.100 mmol), sodium triacetoxyborohydride (0.043 g, 0.201 mmol) and oxetane-3 A solution of -one (0.011 g, 0.151 mmol) in rt (5 mL) was stirred at the same temperature for 18 h. 1.0N hydrochloric acid solution was poured into the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 5%) to give the title compound (0.046 g, 82.7%) in the form of a yellow oil.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (ddd, 1H, J = 7.9, 6.2, 1.7 Hz), 7.71 (td, 1H, J = 9.9, 1.7 Hz), 7.59 (td, 1H, J = 7.6 , 5.4 Hz), 7.22 (dd, 1H, J = 6.5, 2.6 Hz), 7.10 (t, 1H, J = 8.5 Hz), 7.03 (s, 1H), 7.03-6.75 (m, 1H), 4.98 (d , 2H, J = 4.3 Hz), 4.67-4.52 (m, 4H), 3.57-3.44 (m, 1H), 2.94 (s, 2H), 2.44 (d, 8H, J = 60.9 Hz); LRMS (ES) m / z 554.5 (M ⁺ +1).

Example 98 Synthesis of Compound 11621, N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -1- (ox Cetane-3-yl) -N-phenylpiperidine-4-carboxamide

N- (2-fluoro-4- (5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) benzyl) -N-phenylpi prepared in step 5 of Example 31. Ferridine-4-carboxamide hydrochloride (0.150 g, 0.309 mmol), sodium triacetoxyborohydride (0.131 g, 0.619 mmol) and cyclobutanone (0.026 g, 0.371 mmol) were dichloromethane at room temperature. The solution dissolved in phosphorus (10 mL) was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 15%) and concentrated to give N- (4- (5- (difluoromethyl) -1, 3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1- (oxetan-3-yl) -N-phenylpiperidine-4-carboxamide (0.130 g, 83.3%) Was obtained in the form of a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.85 (dd, 1H, J = 8.0, 1.7 Hz), 7.71 (dd, 1H, J = 9.7, 1.7 Hz), 7.56 (t, 1H, J = 7.6 Hz ), 7.41-7.31 (m, 3H), 7.06-6.99 (m, 2H), 5.02 (s, 2H), 4.66 (s, 2H), 4.59 (t, 2H, J = 6.6 Hz), 3.46 (s, 1H), 2.79 (s, 2H), 2.28 (s, 1H), 1.91 (s, 1H), 1.73 (s, 5H); LRMS (ES) m / z 505.2 (M ⁺ +1).

Example 99 Synthesis of Compound 11622, N- (4- (5- (Difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1- (jade Cetane-3-yl) -N-phenylpiperidine-4-carboxamide

N- (4- (5- (difluoromethyl) -1,3,4-oxadiazol-2-yl) -2-fluorobenzyl) -N-phenylpi prepared in step 3 of Example 39 Ferridine-4-carboxamide hydrochloride (0.150 g, 0.321 mmol), sodium triacetoxyborohydride (0.136 g, 0.643 mmol) and cyclobutanone (0.027 g, 0.386 mmol) were dichloromethane at room temperature. The solution dissolved in phosphorus (10 mL) was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO ₂ , 12 g cartridge; methanol / dichloromethane = 0% to 15%) and concentrated to give N- (4- (5- (difluoromethyl) -1, 3,4-oxadiazol-2-yl) -2-fluorobenzyl) -1- (oxetan-3-yl) -N-phenylpiperidine-4-carboxamide (0.130 g, 83.2%) Was obtained in the form of a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (dd, 1H, J = 8.0, 1.7 Hz), 7.70 (dd, 1H, J = 9.8, 1.7 Hz), 7.54 (t, 1H, J = 7.6 Hz) , 7.35 (dd, 3H, J = 4.9, 2.0 Hz), 7.06-6.99 (m, 2H), 6.84 (d, 1H, J = 51.7 Hz), 5.02 (s, 2H), 4.65 (s, 2H), 4.59 (t, 2H, J = 6.5 Hz), 3.45 (s, 1H), 2.78 (s, 2H), 2.28 (s, 1H), 2.03 1.85 (m, 2H), 1.73 (s, 4H); LRMS (ES) m / z 487.2 (M ⁺ +1).

Activity Measurement and Assay Protocols of Compounds of the Invention

< Experimental Example  1> HDAC  Detection of enzyme activity inhibition (in vitro)

In order to confirm the selectivity for the HDAC6 of the compound represented by the formula (I) of the present invention through the HDAC1 and HDAC6 enzyme activity inhibition experiment, a comparative experiment was conducted using the existing development material as a control.

HDAC enzyme activity was measured using the HDAC Fluorimetric Drug Discovery Kit (BML-AK511, 516) from Enzo Life Science. Recombinant human HDAC1 (BML-SE456) for HDAC1 enzyme activity test was used as an enzyme source Fluor de Lys ^ⓡ - was used as the "SIRT1 (BNL-KI177) as a substrate. Dispense 5-fold diluted compounds into 96-well plates, add 0.3 μg of enzyme and 10 μM substrate to each well for 60 minutes at 30 ° C, and add Fluor de Lys ^® Developer II (BML-KI176) for 30 minutes. After finishing, the fluorescence value (Ex 360, Em 460) was measured using a multi-plate reader (Flexstation 3, Molecular Device). HDAC6 enzyme was tested using the same protocol as the HDAC1 enzyme activity test using human recombinant HDAC6 (382180) from Calbiochem. The final result was calculated for each IC ₅₀ value using GraphPad Prism 4.0 program.

As described in Table 2 above, in the activity inhibition test results for HDAC1 and HDAC6, the 1,3,4-oxadiazole amide derivative compound of the present invention, the optical isomer thereof, or a pharmaceutically acceptable salt thereof is about It was confirmed that exhibiting good selective HDAC6 inhibitory activity of 36 to about 3846 fold.

< Experimental Example  2> HDAC6  Specific inhibitors are mitochondria Axon movement  Effect analysis (in vitro)

In the analysis of the effects of HDAC6-specific inhibitors on mitochondrial axon migration, compounds represented by the general formula (I) of the present invention selectively inhibit HDAC6 activity and increase the acetylation of Tubulin, a major substrate of HDAC6, thereby enhancing Amyloid- in neuronal axons. In order to confirm whether the mitochondrial migration speed is reduced by beta treatment to show an improvement effect, a comparative experiment was conducted using the existing development as a control.

Hippocampal neurons were cultured for 7 days in Sprague-Dawley (SD) rat embryos at 17 to 18 days of fertilization in an imaging vessel coated with extracellular matrix and Amyloid-beta protein fragments were maintained at a concentration of 1 M. Treated. After 24 hours, the compound was treated on day 8 of in-flight culture and after 3 hours, MitoTracker Red CMXRos (Life Technologies, NY, USA) was treated for the last 5 minutes to stain mitochondria. Axon migration of stained neuronal mitochondria was performed by confocal microscopy (Leica SP8; Leica microsystems, UK), and images were taken for 1 minute at 1-second intervals, and each mitochondria was moved per second with the IMARIS analysis program (BITPLANE, Zurich, Switzerland) The speed was measured.

As a result, it was confirmed that the 1,3,4-oxadiazole amide derivative compound of the present invention, the optical isomer thereof or the pharmaceutically acceptable salt thereof showed an improvement in mitochondrial axon migration rate.

Claims (11)

1,3,4-oxadiazole amide derivative compound represented by the following formula (I), optical isomers thereof or pharmaceutically acceptable salts thereof: [Formula 1]

In Chemical Formula I, L ₁ , L ₂ or L ₃ are each independently-(C ₀ -C ₂ alkyl)-; Z ₁ to Z ₄ are each independently N or CR ^Z {Wherein Z ₁ to Z ₄ may not be three or more at the same time N, R ^Z Is -H or -X}; R ₁ is —CX ₂ H or —CX ₃ ; R ₂ is-(C ₁ -C ₄ alkyl),-(C ₁ -C ₄ alkyl) -O (C ₁ -C ₄ alkyl),-(C ₁ -C ₄ alkyl) -C (= O) -O (C ₁ -C ₄ alkyl),-(C ₃ -C ₆ cycloalkyl), -aryl, -heteroaryl or

,

or

ego Wherein one or more H of-(C ₃ -C ₆ cycloalkyl), -aryl or -heteroaryl is -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl ), -C (= O) - (C 1 -C 4 alkyl), -C (= O) -0 (C 1 -C ₄ can be substituted with alkyl), or -CF _3, Y is -N-, -O- or -S (= O) _2- , When Y is -N-, R ₄ and R ₈ are each independently -H,-(C ₁ -C ₄ alkyl), -C (= O)-(C ₁ -C ₄ alkyl), -C (= O)-(C ₃ -C ₆ cycloalkyl), -C (= 0) -0 (C ₁ -C ₄ alkyl), -C (= 0) -CF ₃ , -S (= 0) _2- (C ₁ -C ₄ alkyl),-(C ₂ -C ₆ heterocycloalkyl), benzyl or amine protecting group, wherein-(C ₂ -C ₆ heterocycloalkyl) contains N, O or S atoms in the ring You can}}, When Y is -O- or -S (= O) _2- , R ₄ and R ₈ are nothing (null), R ₅ to R ₈ are each independently —H, — (C ₁ -C ₄ alkyl), —OH, —CH ₂ OH or —C (═O) —NH ₂ , a to c are each independently an integer of 1, 2 or 3; R ₃ is -H,-(C ₁ -C ₄ alkyl),-(C ₁ -C ₄ alkyl) -O (C ₁ -C ₄ alkyl),-(C ₁ -C ₄ alkyl) -C (= 0 ) -O (C ₁ -C ₄ alkyl),-(C ₃ -C ₆ cycloalkyl), -aryl, -heteroaryl,

or

ego {Wherein at least one H of-(C ₃ -C ₆ cycloalkyl), aryl or heteroaryl is each independently -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl), -C (= O) - (C 1 -C 4 alkyl), -C (= O) -0 (C 1 -C _4, and may be substituted with alkyl), or -CF _3, R ₄ , R ₅ , R ₆ , Y, a, b, R ₁ , L ₁ , Z ₁ , Z ₂ , Z ₃ and Z ₄ are as defined above; And X is F, Cl, Br or I. The compound of claim 1, wherein In Chemical Formula I, L ₁ and L ₃ are-(C ₀ alkyl)-; L ₂ is-(C ₁ -C ₂ alkyl)-; Z ₁ to Z ₄ are each independently N or CR ^Z {Wherein Z ₁ to Z ₄ may not be two or more N at the same time, R ^Z Is -H or -X}; R ₁ is —CX ₂ H or —CX ₃ ; R ₂ is — (C ₁ -C ₄ alkyl),-(C ₃ -C ₆ cycloalkyl), -aryl, -heteroaryl,

,

or

ego Wherein one or more H of-(C ₃ -C ₆ cycloalkyl), -aryl or -heteroaryl is -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl ), -C (= O) - (C 1 -C 4 alkyl), -C (= O) -0 (C 1 -C ₄ can be substituted with alkyl), or -CF _3, Y is -N-, -O- or -S (= O) _2- , When Y is -N-, R ₄ and R ₈ are each independently -H,-(C ₁ -C ₄ alkyl), -C (= O)-(C ₁ -C ₄ alkyl), -C (= _{O) -CF 3, -S (=} O) 2 - (C 1 -C 4 alkyl), - (C ₂ -C ₆ heterocycloalkyl), -C (= O) - (C 3 -C 6 cycloalkyl ), Benzyl or amine protecting group, wherein-(C ₂ -C ₆ heterocycloalkyl) may contain O atoms in the ring; When Y is -O- or -S (= O) _2- , R ₄ and R ₈ are nothing (null), R ₅ to R ₈ are each independently —H, — (C ₁ -C ₄ alkyl), —OH, —CH ₂ OH or —C (═O) —NH ₂ , a to c are each independently an integer of 1, 2 or 3; R ₃ is -aryl or -heteroaryl {Wherein at least one H of aryl or heteroaryl is each independently -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl), -C (= 0)-( C ₁ -C ₄ alkyl), -C (= 0) -0 (C ₁ -C ₄ alkyl) or -CF ₃ ; And X is F, Cl, Br or I, 1,3,4-oxadiazole amide derivative compound represented by formula (I), its optical isomer or pharmaceutically acceptable salt thereof. The compound of claim 2, wherein In Chemical Formula I, L ₁ and L ₃ are-(C ₀ alkyl)-; L ₂ is-(C ₁ alkyl)-; Z ₁ to Z ₄ are each independently N or CR ^Z {Wherein Z ₁ to Z ₄ may not be two or more N at the same time, R ^Z Is -H or -X}; R ₁ is —CF ₂ H or —CF ₃ ; R ₂ is — (C ₁ -C ₄ alkyl), -pyridinyl or

ego Wherein one or more H of -pyridinyl is -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl), -C (= 0)-(C ₁ -C ₄ alkyl), -C (= O) -0 (C 1 -C _4, and may be substituted with alkyl), or -CF _3, Y is -N-, R ₄ is — (C ₁ -C ₄ alkyl), —C (═O)-(C ₁ -C ₄ alkyl) or -S (═O) _2- (C ₁ -C ₄ alkyl), R ₅ or R ₆ are each independently —H or — (C ₁ -C ₄ alkyl), a and b are each independently an integer of 1 or 2}; R ₃ is -aryl Wherein one or more H of aryl may each independently be substituted with -X; And X is F, Cl, Br or I, 1,3,4-oxadiazole amide derivative compound represented by formula (I), its optical isomer or pharmaceutically acceptable salt thereof. The compound of claim 3, wherein In Chemical Formula I, L ₁ and L ₃ are-(C ₀ alkyl)-; L ₂ is-(C ₁ alkyl)-; Z ₁ to Z ₄ are each independently N or CR ^Z {Wherein Z ₁ to Z ₄ may not be two or more N at the same time, R ^Z Is -H or -X}; R ₁ is —CF ₂ H or —CF ₃ ; R ₂ is -pyridinyl or

ego Wherein one or more H of -pyridinyl is -X, -OH,-(C ₁ -C ₄ alkyl), -O (C ₁ -C ₄ alkyl), -C (= 0)-(C ₁ -C ₄ alkyl), -C (= O) -0 (C 1 -C _4, and may be substituted with alkyl), or -CF _3, Y is -N-, R ₄ is — (C ₁ -C ₄ alkyl), —C (═O)-(C ₁ -C ₄ alkyl) or -S (═O) _2- (C ₁ -C ₄ alkyl), R ₅ or R ₆ are each independently -H, a and b are each independently an integer of 1 or 2; R ₃ is -aryl Wherein one or more H of aryl may each independently be substituted with -X; And X is F, Cl, Br or I, 1,3,4-oxadiazole amide derivative compound represented by formula (I), its optical isomer or pharmaceutically acceptable salt thereof. The 1,3,4-oxadiazole amide derivative compound represented by Formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound represented by Formula (I) is a compound shown in the following table. :

The compound represented by formula (I) is a 1,3,4-oxadiazole amide derivative compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is a compound shown in the following table. :

The 1,3,4-oxadiazole amide derivative compound represented by Formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 6, wherein the compound represented by Formula (I) is a compound shown in the following table. :

A pharmaceutical for preventing or treating a histone deacetylase-mediated disease comprising as an active ingredient a compound represented by the formula (I) according to any one of claims 1 to 7, or an optical isomer thereof or a pharmaceutically acceptable salt thereof. Composition. The method of claim 8, wherein the histone deacetylase-mediated disease is an infectious disease, neoplasm, endocrine, nutritional and metabolic diseases, mental and behavioral disorders, neurological diseases, eye and appendage diseases, circulatory diseases, respiratory diseases, Pharmaceutical composition for the prevention or treatment of diseases of the digestive system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue or congenital malformations, deformations and chromosomal abnormalities. A method for treating a histone deacetylase-mediated disease comprising administering a therapeutically effective amount of a compound represented by formula (I) according to any one of claims 1 to 7 or an optical isomer thereof or a pharmaceutically acceptable salt thereof. How to treat. Use of a compound represented by formula (I) according to any one of claims 1 to 7, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prophylaxis or treatment of histone deacetylase mediated diseases.